Cancer

Do you know what is breast cancer? Breast cancer is a malignant tumour that develops from cells in the breast. How breast cancer spreads to other parts of the body? The cancer cells grow and divide out of control, invading and damaging nearby tissues and organs. Cancer cells also break away from the original tumour and enter the bloodstream or lymphatic system. This spread of the cancer is called metastasis. Breast cancer may appear as a lump but there are many different types of breast lumps. Most lumps are harmless, or benign.

Benign lumps are abnormal, but not life-threatening. Who is at most risk? Men? Female? Or both of them will get breast cancer? The answer is female and male will get breast cancer. However, breast cancer is a female diseases, percentage of men get breast cancer is very low. For example, In Malaysia, the National Cancer Registry reported 56 news cases of male breast cancer in 2002 ; About 1% of cases occur in men (around 300 per year in the UK). For female, the percentage of Malaysian women get breast cancer is 30% in 2002 and 31% in 2003.

What are the causes of breast cancer? A woman’s risk of getting breast cancer increases with age. More than 80% of cases occur in women over 50. If you have one close relative such as mother and sister with breast cancer, it will doubles up your risk of getting breast cancer. Most cancer patients may not have a family history of the cancer, nor any exposure to known environment trigger. Women who have received high-dose ionizing radiation to the chest have a relative risk of breast cancer.

Besides that, taking alcohol such as more than one glass per day to an increased risk of breast cancer. Taking the contraceptive pill slightly increase the risk too. Taking hormone replacement therapy significantly increases your risk somewhat more, but the health benefits derived from hormone replacement are better overall. What are the symptoms of breast cancer? Early breast cancer can in some cases present a breast pain or a painful lump. Another reported symptom complex of breast cancer is Paget’s disease of the breast.

This syndrome presents as eczematoid skin changes at the nipple, and is a late manifestation of an underlying breast cancer. In the simple ways, female should check for these main symptoms such as change in the size or shape of a breast, dimpling of the breast skin, the nipple becoming inverted and swelling or a lump in the armpit. If you found that you unfortunately get breast cancer, what should you do? Don’t forget breast cancer has many types of treatment! The main treatment of breast cancer is surgery.

In the most cases, conservative surgery is used, which preserves the shape and the appearance of the breast. For very early breast cancer, only the lump and a small area of tissue around it is removed. For later stage breast cancer, much more tissue is removed but it is replaced with muscle to rebuild the breast. Since breast cancer cells usually spread first to the lymph node in the armpit, the surgeon will usually cut into it to check for any spread. The surgery may followed by a short course of radiotherapy or chemotherapy, depending on the type of tumour and how advanced it is.

In the most cases, the patient will given a longer course of hormone therapy like tamoxifen which reduces the risk of the cancer recurring. The other treatments are radiation treatment and mammography. In conclusions, breast cancer is a common cancer and it is the second leading cancer killer in female. So, we must always protect ourselves from breast cancer. For me, I suggest that everyone with a family history of breast cancer should check themselves regularly. Thank you.

There are many product categories that could use the Scion marketing approach to apply to their businesses. Music industries market certain bands and artists to appeal more towards a younger age group, computer businesses market upcoming technology to younger audiences, as do phone company ices, websites, and home dcord. Choosing a target market is imperative for businesses in order to focus their advertising to whom they believe they would sell more product to.

On the other hand, the tourism industry is marketing more towards people who are in the retirement age, and cars like vans and Subs focus more on middle age people who probably have children. Different products should be marketed towards who would be most interested, and in a lot of cases, this means businesses must gear their different products towards varying age groups. L]Decoupage buyers might view companies that their parents and grandparents are interested in as “not cool” or too mainstream for their own liking.

Companies can overcome this, however, by changing their consisting in order to appeal to a newer generation. By creating new advertising campaigns and changing what kind of message they want their image to convey, companies have the ability to change the views of younger people. Myself, for example, always thought Subs were for married people with children, but Scion and other comma nines like Toyota have geared commercials to appeal to people my age. Toyota had myself fooled for a long time when they were marketing the Scion, and also thought it was a new brand.

People from the newer generation look for products that are going to allow them to show their personality, and not just be another face among the crowd. Scion was smart to use the whole customization aspect of the Scion, especially because people my age and younger are always changing their cars to be what they want them to be, and not be what comes off the lot. If Scion doesn’t find a way to still stay new, I do believe that the allure of having a Scion will eventually wear off.

Businesses should always be ware that their target audiences are always changing, and must be on top of what it happening in the world in order to keep their businesses alive and growing. By promoting customer communications and knowing what the younger generations want in a product, Scion could possibly still keep their appeal. It is going to be hard, though. Every time I see a Scion I already think that their idea is kind of old.

“There are a thousand excuses for failure, but never a good reason”, I agree. Some psychologists think that bad and good habits people get through lifetime period. If so, then people can get rid of undesirable habits, but how? Some people would say that to get rid of bad habits is easy when person has a desire. Also, some will say that who love God can rely on his help and blessing. However, a lot of people would say that it is not that easy to kick a bad habit.

In fact, bad habits affect our lives actively, but when person follow these steps, she can easily overcome a problem. First of all, people should find a motivation to stop a bad habit. A person who has a motivation is always looking for solutions while others are looking for reasons and excuses. Before person makes any bad move in her life, she should ask herself one question: “For what or for whom I should stop doing a bad habit? ” A lot of people would say that it is not worth it. However, some people would stop their bad habit for the loved ones.

For example, there is could be internal reason for solving this robber. People often break bad habits because they do not want to spoil their children. Moreover, children usually pick up bad habits from parents and peers. To prevent that unlikable situation, parents would do their best for break a habit. Also, smoking is a cause of heart and lung diseases. Moreover, smoking can cause a cancer. 90% of lung cancer patients developed their disease because of smoking. There is, also, external reason for motivation. For example, smoking is a cause of yellow teeth, super dry skin and breaking hair.

Smokers often are nervous, irritable, old not focus their thoughts, and could not sleep well. These causes affect peoples social life in many ways. Therefore, smokers have difficulties in Job interviews and relationships because they have low self-esteem and self-confidence. All in all, West Virginia University about the bad habits say:” if you want to quit smoking, you should focus on decreasing your risk of lung cancer and heart disease. If you are driven by positive motivation, think of how much whiter your teeth will be and how much more breath you will have when you climb stairs.

Also, you will save some money by not eying cigarettes. ” Second, create conditions and be away from people who have bad addictions. People learn the features of behavior in their environment. It is very difficult to deny alcohol in the cheerful company of friends. In Russia, for instance, when people are visiting each other at home, they should drink three shots of vodka before they enter the house. However, even when person is not drinking at all, householder finds it unrepeatable and would not ask that person to come to his house again.

Another example, at the party there are two groups: in-group and out- roof. In-group people are those who run the party. Of course, alcohol is included for this group. However, people from out-group do not have bad addictions. In-group can make bad Jokes and encourage drinking, and out-group does not feel themselves such as all, so they Just can give up. Nevertheless, not only alcohol can make people in-group. Furthermore, if person is attractive, interesting and outgoing, he do not need alcohol to be in-group. Briefly, to be separated from those who have bad habits, does not mean to be away from them.

It is mean, that people should put a task in heir head, for do not give up on the goal to break a habit.. That is how people separate themselves at parties. Briefly, people should follow some quote in life, for pushing themselves for something valuable. Third, people should never give up, but go to their target to the end. People should not be disappointed after the first obstacle. This is not the end of the world. Nothing comes easy, especially when people are trying to get rid of bad habits that exist in their lives. For instance, I knew the girl Katherine. She was drinking beer every single night.

Katherine wasn’t aware of her problem until she got an addiction to alcohol. Moreover, she lost communication with her friends. For them, she was simply alcoholic. She was like a blind Capitan who can not notice a leak in the vessel until it finally sinking. Soon, Katherine understood that she needs to get rid of her addiction. For this purpose, Katherine started looking for a solution. After a lot of tries, she finally found a solution. Instead of bottle of beer, she was drinking a glass of orange Juice. There were a lot of doubts from her friends that she not going to cake it.

They Just did not believe in her. Although, she did not give herself up, but was fighting with her bad habit till it gone. Indeed, Katherine throws away a bad habit of her because she believed in herself. Fourth, do not make any exceptions. When people decide to kick bad habits, in any case or situations do not give concessions. Once people start thinking: “Oh, today is a nervous day, so I can smoke one cigarette”, or “l would not gain weight if I will have some ice-cream. ” Our bad habits begin to fight for a place in people’s life. When people make exceptions, it s an illusion to break a bad habit.

The number of exceptions will increase every day until the bad habit will not take his place again. For example, humans can imagine that our good and bad habits like two wolves that always are fighting with each other. Who will win? Answer is the wolf whom you feed will win. Nevertheless, stop feed and give support to a bad habit. “If you do not pour water on your plant, what will happen? It will slowly wither and die. Our habits will also slowly wither and die away if we do not give them an opportunity to manifest. You need not fight to stop a habit.

Just don’t give it an opportunity to repeat itself. (67)” ? Swami Statisticians, The Yoga Sutras. Last step is to imagine you without a bad habit. Just turn an imagination, and you will see yourself succeed. The people are very likable to a person without a bad habit. People don’t like see you hiding your hands because of bitten nails or smell the cigarette smoke from someone’s mouth. Let it all go! Imagine, when you are going to give a speech in front of many people, you would not stammer in front of audience, but behave discreetly and fluently. Imagination acts as hypnosis.

If a person presents himself without bad habits, he subconsciously is hypnotize himself to quit one. As a result, a person could get rid of the bad habit. For instance, I was biting my nails. I wanted to quit hundreds of times, but couldn’t. Then I started imagine myself as a bride, but how bride would have bitten nails in the ceremony? How the groom would put the ring on the bride hand? Consequently, I quit biting my nails. In short, imagination helped me to get rid of nail biting problem. Imagination set a desire to be better person, and to increase in someone’s eyes.

TO conclude, bad addictions cause an unpleasant influence in our life. Bad habits have negative impact on people’s health and social life. However, people can overcome them by find a motivation, create conditions and be away from people with bad habits, never give up, do not make any exceptions, and turn imagination in which there is no place for a bad habit. “Bad habits are like a comfortable bed, easy to get into, but hard to get out of. ” ?Unknown. If people would follow these steps, they can kick bad habits very willingly.

Association of CYP3A4 in cancer occurrence severity and drug metabolism Abstract The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated with prostate cancer occurrence and severity. It has been estimated that up to 60% of the variability in CYP3A4 activity may be because of a genetic component. A SNP in the nifedipine-specific response element in the promoter of the CYP3A4 gene (alternatively termed eg. -392AG, CYP3A4-V, CYP3A41B).

Case studies of Caucasians and of African-Americans have detected associations between CYP3A41B and presentation with biologically aggressive disease. It has been postulated that the presence of the CYP3A41B allele decreases the amount of CYP3A4 protein, leading to a reduction of testosterone metabolism and, therefore, more availability of testosterone for conversion to dihydrotestosterone, the most potent androgen affecting the growth and differentiation of prostate cells, including an intronic SNP that affects splicing of the CYP3A5 transcript.

The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity. Also variability in CYP3A4 function was determined noninvasively by the erythromycin breath test (ERMBT) and lead to the detection of role of CYP3A4 in causing prostate and breast cancer. Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for phase I drug metabolism of many anticancer agents.

It is also a major route for metabolism of many drugs used by patients to treat the symptoms caused by cancer and its treatment as well as their other illnesses, for example, cardiovascular disease. Advanced cancer patients are on multiple medications for symptom management and co-morbidities. Pharmacokinetic drug interactions occur with absorption, drug–protein binding, metabolism, and elimination. By far the most prevalent and dangerous drug–drug interactions occur through cytochrome metabolism.

Drug metabolism is through the cytochrome system (phase I) and/or through conjugation (phase II). Cyto- chromes oxidize, demethylate, or hydroxylate substrate medications and conjugases increase drug solubility by adding glucuronides, amino acids, or sulfate subgroups that facilitate elimination. In this review, I also examine the role of specific P450 enzymes in the metabolism of anticancer drugs in humans and discuss some significant interactions that often appear to result from inhibition of anticancer drug metabolism.

The available evidence, however, strongly suggests that certain drugs influence the pharmacokinetics of anticancer agents also (and perhaps primarily) by acting as P-glycoprotein inhibitors, thereby inhibiting P-glycoprotein mediated drug elimination. CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e. g. , analgesics) and side effects (e. g. , antiemetics and antidiarrheals) and to treat comorbidities. The anti- cancer drugs metabolized by CYP3A4 include docetaxel (Marre et al. , 1996), cyclophosphamide (Chang et al. 1993), ifosfamide (Walker et al. , 1994), etoposide (Kawashiro et al. , 1998), tamoxifen (Crewe et al. , 1997), irinotecan (Santos et al. , 2000), vinblastine (Zhou-Pan et al. , 1993), and vinorelbine (Kajita et al. , 2000). Although there is a marked interindividual variation of pharmacokinetic parameters be-tween patients (Evans and Relling, 1999), and such variation in patient response is often attributed to polymorphism in P450 genes, CYP3A4 is an exception because only a small percentage of the variation in activity can be attributed to genotype (Lamba et al. , 2002a,b).

Introduction

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. 14. 13. 97), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver. Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body where it may play an important role in metabolism.

Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown. The CYP3A genes lie in a region of chromosome 7q21-q22 as part of a multigene family, including CYP3A4, CYP3A5, CYP3A7, CYP3A43 in addition to psuedogenes. Only CYP3A4, CYP3A5, CYP3A7, and CYP3A43 are expressed in adults. These loci seem to be in linkage disequilibrium. [pic] While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo.

It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates. CYP3A4 is responsible for the oxidative metabolism of a wide variety of xenobiotics, including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients.

CYP3A4 is expressed in the prostate, breast, gut, colon, and small intestine, but its expression is most abundant in the human liver, accounting for 30 percent of the total CYP protein content. It exhibits a broad substrate specificity and is responsible for oxidation of many therapeutic drugs and a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In liver microsomes, it is involved in a nicotinamide adenine dinucleotide phosphate-dependent electrontransport pathway.

Prostate cancer is an abnormal, uncontrolled growth of cells that results in the formation of a tumor in the prostate gland. Prostate cancer begins most often in the outer part of the prostate. It is the most common cancer in men older than age 50. In most men, the cancer grows very slowly. Genes involved in androgen metabolism have been implicated in the etiology of prostate cancer. Testosterone is a major determinant of prostate growth and differentiation. Testosterone bioavailabilty is determined by a number of enzymes, including CYP3A4 and CYP3A43.

CYP3A4 is involved in the oxidation of testosterone to 2-, 6-, or 15-hydroxytestosterone (which is less biologically active than testosterone or dihydrotestosterone. CYP3A43 also exhibits testosterone 6-hydroxylation in vitro and is predominantly expressed in the prostate. Variants that affect CYP3A4 activity could therefore alter prostate tumor occurrence or aggressiveness. A variant in the 5’untranslated region of CYP3A4 (denoted CYP3A4*1B) has been associated with prostate cancer in three studies.

A mutation in CYP3A4 may lead to a reduced potential for oxidizing testosterone, leaving a greater bioavailability of the hormone to be metabolized intracellularly to its biologically active form of dihydroxytestosterone, the principal androgenic hormone involved in regulating prostate growth. Clinical evidence exists that androgens are related to the growth and development of prostate cancers, and Androgen ablation in men with hormone-sensitive prostate tumors reduces tumor size and decreases the associated disease burden.

This evidence suggests that the metabolism of testosterone into the more biologically active forms of the hormone may be important in determining prostate cancer risk. Medications are metabolized and secreted through the liver, gastrointestinal tract, and kidneys, all of which contain cytochrome enzymes for this purpose. The kidneys do not efficiently eliminate lipophilic drugs that are readily reabsorbed across tubular membranes in the distal renal collecting system; conjugation of drugs improves solubility and drug elimination.

Lipid-soluble agents are first metabolized by two reactions termed phase I and phase II before being eliminated. The phase I enzymes most frequently involved are cytochromes CYP3A4/3A5, CYP2D6, CYP2C9, CYP2C19 . Cytochrome-induced oxidation hydroxylation and demethylation proceeds by initial binding of drug to the oxidized form of cytochrome P450, and then coupling NADPH-bound oxygen to the cytochrome P450 oxidoreductase. Common medications used in palliative medicine (dexamethasone, prednisone, midazolam, triazolam, alprazolam, methadone, fentanyl, and haloperidol) are substrate drugs for CYP3A4.

Certain anti-seizure drugs, selective serotonin receptor inhibitors, macrolides, and azoles either upregulate or inhibit CYP3A4 enzyme activity. Protease inhibitors and nucleoside or non-nucleoside analogs used for anti-retroviral therapy can both inhibit enzyme activity and/or upregulate CYP3A4 expression.

Factors influencing drug interactions of CYP3A4

• Recipient drug concentrations
• Enzyme saturation relative to concentration of recipient drug at enzyme site
• Substrate drug affinity for the enzyme (Km) and enzyme capacity (Vmax)
• Homotropic enzyme interactions by recipient drug Concentration of the precipitant drug in liver vs plasma
• Inhibition constant relative to inhibitor concentration
• Precipitant drug interactions at both promoter site and the structural enzyme site
• Liver concentration of precipitant drug and recipient drug(recipient and precipitant drug) clearance through multiple organs or cytochromes
• Contribution of P-glycoprotein to recipient and precipitant drug metabolism and elimination
• Genetically determined expression of CYP3A4 governed by the promoter site.

Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. As xamples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.

Studies have shown that P450 enzymes are expressed not only in the liver and extrahepatic tissues but also in different kinds of tumours. For example, the prodrugscyclophosphamide and ifosfamide need to be activated by specific P450 enzymes to produce cytotoxic compounds, and, if these enzymes were also found in the tumour, local activation of the drug could be important for efficacy. In selected cases, it might even be possible to enhance drug activation through modulation of the appropriate P450 enzyme(s).

If bioactivation in the liver is predominant, the question arises whether the active metabolite(s) can achieve effective concentrations in the tumour. The delivery of the drug or the active metabolites into the tumour may be inadequate, for instance, due to the physicochemical nature of the compound or poor vascularization of the tumour. When evaluating the potential significance of drug interactions with anticancer drugs, the key question is whether such interactions could affect, at least in selected cases, the overall clinical response or toxicity of the drug.

In general, the pharmacological properties of anticancer drugs (e. g. steep dose-response curves and low therapeutic indices) suggest that even small changes in the pharmacokinetic profile could significantly alter toxicity or efficacy. Material and Methods Lehmann et al. (1998) identified a human orphan nuclear receptor, termed the pregnane X receptor, that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. It is inducible by a variety of agents including glucocorticoids and phenobarbital.

It appears to play a central role in the metabolism of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin. It also catalyzes the 6-beta-hydroxylation of a number of steroids including testosterone, progesterone, and cortisol. As indicators of CYP3A4 function in the evaluation of transplant recipients, measurement of erythromycin metabolism by a breath test (Elshourbagy and Guzelian, 1980) and the presence of 6-beta-hydroxylated steroids in urine have been used. This has led to study the role of CYP3A4 in causing prostate cancer.

Similar experiments were performed for females which showed its role in the occurrence of breast cancer. Shet et al. (1993) reported the results of experiments designed to evaluate the enzymatic properties of a purified recombinant fusion protein containing the heme domain of human CYP3A4. Epipodophyllotoxins, which are used as DNA topoisomerase II inhibitors in the treatment of leukemia and are associated with the production of translocations involving the MLL gene as well as of other translocations, are substrates for metabolism by CYP3A. Rebbeck et al. 1998) identified a variant in the 5-prime promoter region of the CYP3A4 gene: a polymorphism in the nephedipine-specific response element of the gene. They referred to the polymorphism as CYP3A4-V or CYP3A4*1B. There are several pathways involved in the metabolism of testosterone, and the genes that regulate these pathways, including 5-alpha-reductase-2 (SRD5A2) and CYP3A4, have been implicated in prostate cancer susceptibility. The CYP3A4*1B allele may decrease the oxidative deactivation of testosterone (Rebbeck et al. , 1998). African Americans have the highest documented rates of prostate cancer in the world.

Zeigler-Johnson et al. (2002)studied differences in genotypes at the SRD5A2 and CYP3A4 loci according to ethnicity. They found that the CYP3A4*1B allele was more common in Ghanaians and African Americans (gene frequency more than 50%) than in Caucasians (less than 10%), and was apparently nonexistent in Asians. Schirmer et al. (2006) investigated the CYP3A locus in 5 ethnic groups. The degree of linkage disequilibrium (LD) differed among ethnic groups, but the most common alleles of the conserved LD regions were remarkably similar.

Non-African haplotypes were few; for example, only 4 haplotypes accounted for 80% of common European Caucasian alleles. Large LD blocks of high frequencies suggested selection. European Caucasian and Asian cohorts each contained a block of single-nucleotide polymorphisms with very high P excess values. The overlap between these blocks in these 2 groups contained only 2 of the investigated 26 SNPs, and 1 of them was the CYP3A41B allele. The region centromeric of CYP3A4*1B on 7q exhibited high haplotype homozygosity in European Caucasians as opposed to African Americans.

CYP3A4*1B showed a moderate effect on CYP3A4 mRNA and protein expression, as well as on CYP3A activity assessed as V(max) of testosterone 6-beta-hydroxylation in a liver bank. Selection against the CYP3A4*1B allele in non-African populations was suggested. The elimination of this allele involved different parts of the CYP3A locus in European Caucasians and Asians. Because CYP3A4 is involved in vitamin D metabolism, Schirmer et al. (2006) raised the possibility that rickets might be the underlying selecting factor.

By genotyping liver samples from 18 Caucasian donors at 2 SNPs (78013C-T and 78649C-T) in intron 7 of CYP3A4, Hirota et al. (2004) demonstrated a correlation between the total CYP3A4 mRNA level and allelic expression ratio, defined as the relative transcript level ratio derived from the 2 alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the 2 alleles, revealed extremely low levels of total hepatic CYP3A4 mRNA, and thus low metabolic capability as assessed by testosterone 6-beta-hydroxylation.

A broad specificity coupled with high levels of expression in the liver means it is responsible for the metabolism of more than half of all prescribed drugs (Guengerich, 1997). When patients receive several medications concurrently, unwanted and life-threatening effects can result from the competition for the same drug-metabolizing enzyme affecting the blood levels of the competing drugs. Cancer patients would seem to be significantly at risk in this respect, because CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e. g. analgesics) and side effects (e. g. , antiemetics and antidiarrheals) and to treat comorbidities. The anti-cancer drugs metabolized by CYP3A4 include docetaxel (Marre et al. , 1996), cyclophosphamide (Chang et al. , 1993), ifosfamide (Walker et al. , 1994), etoposide (Kawashiro et al. , 1998), tamoxifen (Crewe et al. , 1997), irinotecan (Santos et al. , 2000), vinblastine (Zhou-Pan et al. , 1993), and vinorelbine (Kajita et al. , 2000). [pic] Cyclophosphamide and ifosfamide Cyclophosphamide and ifosfamide are alkylating anticancer agents that require biotransformation to produce pharmacologically active, cytotoxic compounds.

Chang and colleagues demonstrated that CYP2B6 and CYP3A4 are the major isoforms catalyzing cyclophosphamide and ifosfamide 4-hydroxylation (that is, activation), respectively, in human liver. Walker et al. recently showed that CYP3A4 makes a significant contribution to both the activation and N-dechloroethylation of ifosfamide in human liver. Ifosfamide (IF) is a widely used antitumor prodrug that is effective against solid tumors such as sarcomas and hematologic malignancies.

Major clinical toxicities include urotoxicity, nephrotoxicity and neurotoxicity (occurs in approximately 20% of patients). On the other hand, IF has lower myelotoxicity relative to its structural analog, cyclophosphamide. Glomerular and tubular dysfunctions represent serious side effects, especially in children who are co-treated with other nephrotoxic drugs. This diagram, which shows the genes involved in the biotransformations of IF and its metabolites, includes pathways of activation, deactivation and toxicity.

The metabolism of IF is parallel to that of cyclophosphamide but with some differences in isozyme specificities and reaction kinetics. Activation of IF to 4-hydroxyifosfamide is catalyzed by the hepatic cytochrome P450 (CYP) isoform CYP3A4 with 2A6, 2B6, 2C8, 2C9 and 2C19 making more minor contributions. Competing with 4-hydroxylation is a major (up to 50% or more) oxidative pathway that results in dechloroethylation and the formation of chloroacetaldehyde (neurotoxic) and 2- or 3-dechloroethylifosfamide (primarily mediated by CYP2B6 and CYP3A4). -Hydroxyifosfamide rapidly interconverts with its tautomer, aldoifosfamide. It is likely that both of these metabolites passively diffuse out of hepatic cells, circulate, and then passively enter other cells. Aldoifosfamide partitions between ALDH1A1-mediated detoxification to carboxyifosfamide and a spontaneous (non-enzymatic) elimination reaction to yield isophosphoramide mustard (IPM) and acrolein (associated with bladder toxicity).

IPM, the DNA crosslinking agent of clinical significance, is a circulating metabolite but the anionic IPM does not enter cells as readily as its metabolic precursors. Thus, the intracellular generation of IPM from aldoifosfamide is generally believed to be important to a therapeutic result. Multiple IF metabolites can react with glutathione (GSH) resulting in the formation of various conjugates at different sites along the pathway. Some of these reactions with GSH may be reversible while others are irreversible; the latter are associated with detoxification pathways.

Large interpatient differences, which may be up to seven-fold, in the pharmacokinetics and biotransformation of IF have been reported; however, there has been little reported about genetic variations that may influence varied response to IF treatment. Like cyclophosphamide, IF is chiral at phosphorus but unlike the case for cyclophosphamide, enantioselectivity in IF metabolism may have clinical significance. This is particularly relevant to the distribution of 4-hydroxylation versus N-dechloroethylation products and the impact of this on the CNS toxicity associated with IF therapy.

The differences in the metabolism and disposition of the R- and S-enantiomers of IF have not been fully evaluated in human tissues. Nevertheless, in several studies using characterized human liver microsomes or cDNA-expressed isozymes it has been shown that (R)-IF is subject to less dechloroethylation and more rapid 4-hydroxylation relative to the (S)-IF. Cyclophosphamide (CP) is a widely used antitumor prodrug that is effective against a broad spectrum of human cancers including breast cancer and lymphomas.

The toxicity profile is characterized by myelosuppression and urotoxicity. This diagram shows the genes involved in the biotransformation of CP and its metabolites and includes pathways of activation, deactivation and toxicity. Activation of CP to 4-hydroxycyclophosphamide is catalyzed by the hepatic cytochrome P450 (CYP) isozymes CYP2B6, 2C9 and 3A4 (with 2A6, 2C8 and 2C19 making more minor contributions). Competing with C-4 hydroxylation of CP is a minor (~10%) oxidative pathway that leads to N-dechloroethylation and the formation of the neurotoxic chloroacetaldehyde.

CYP3A4 is primarily responsible for this undesirable side-chain oxidation with a minor contribution from CYP2B6. 4-Hydroxycyclophosphamide interconverts rapidly with its tautomer, aldophosphamide and it is likely that both of these metabolites passively diffuse out of hepatic cells, circulate, and then passively enter other cells. Aldophosphamide undergoes a spontaneous (non-enzymatic) elimination reaction to yield phosphoramide mustard (PM) and acrolein (associated with bladder toxicity).

PM, which is generally believed to be the DNA crosslinking agent of clinical significance, is a circulating metabolite with its anionic form not entering cells very easily. Thus, the intracellular generation of PM from aldophosphamide is believed to be important to a therapeutic result. A major detoxification route is the oxidation of aldophosphamide to the inactive carboxyphosphamide by ALDH1A1 and, to a much lesser extent, by ALDH3A1 and ALDH5A1. Multiple CP metabolites can react with glutathione (GSH) resulting in the formation of various conjugates at different sites along the pathway.

Some of these reactions with GSH may be reversible while others are irreversible; the latter are associated with detoxification pathways. Several-fold differences in the extent of metabolite formation have been observed among patients and these inter-individual differences may be due to polymorphisms in CYP enzymes. There are reports of association between CYP3A4 and 3A5 genotypes and response or survival in patients treated with CP. Many of the genetic variants that affect CP metabolism may still be unknown and further evidence of these variants will be needed to better assess clinical outcomes.

It is noteworthy that CP is chiral at phosphorus and is administered as a racemate; however, enantioselectivity in the metabolism of CP does not appear to result in clinical significance.

Irinotecan

This pathway shows the biotransformation of the chemotherapy prodrug irinotecan to form the active metabolite SN-38, an inhibitor of DNA topoisomerase I. SN-38 is primarily metabolized to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Irinotecan is used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. pic] There is large interpatient variability in response to irinotecan, as well as severe side effects such as diarrhea and neutropenia, which might be explained in part by genetic variation in the metabolic enzymes and transporters depicted here. Well-known variants to effect this pathway are the promoter polymorphic repeat in UGT1A1 (UGT1A128) and the 1236C>T polymorphism in ABCB1. While UGT1A1*28 genotype has been associated with toxicity, further evidence is needed to describe the roles of ABCB1 variants in toxicity.

Epipodophyllotoxins

Relling et al. recently showed that catechol formation by O-demethylation from teniposide and etoposide is primarily mediated by CYP3A4 in human liver. Several substrates for CYP3A4 (e. g. midazolam, erythromycin and cyclosporin) were identified as strong inhibitors of catechol formation from both etoposide and teniposide. The extent of contribution of 0-demethylation to the overall in vivo elimination of these agents is not known, but catechol formation appears to play only a relatively small role in the metabolism of the epipodophyllotoxins.

However, the catechols of epipodophyllotoxins are cytotoxic, and it has been suggested that cytotoxic concentrations of the catechol metabolites might be achieved clinically. Etoposide and teniposide, the epipodophyllotoxins, stabilize the double stranded DNA cleavage normally catalyzed by topoisomerase II and inhibit faithful religation of DNA breaks (PMID: 1681541; 9748545). These double-strand DNA breaks subsequently trigger the desired antitumor effects of the drugs. Metabolism of etoposide is mediated by CYP3A4 and CPY3A5 (PMID: 8114683; 15319341), both of which are transcriptionally regulated by NR1I2 i. e. Pregnane X receptor). Thus, xenobiotics that modulate NR1I2 activity (e. g. dexamethasone and rifampicin) have been observed to enhance etoposide clearance (PMID: 15578943; 12969965). In addition to CYP3A4/5 mediated reactions, conversion of etoposide to the O-demethylated metabolites (catechol and quinone) can also be catalyzed by prostaglandin synthases or myeloperoxidase.

Glutathione and glucuronide conjugation appear to inactivate parent drug and metabolite, and are mediated by GSTT1/GSTP1 and UGT1A1, respectively (PMID: 1315544; 3167829; 17151191; 12695346). Efflux of conjugated or unconjugated forms of etoposide has been associated with ABCC1, ABCC3 and ABCB1 (PMID: 8640791; 11581266), representing plausible mechanisms of drug resistance. Epipodophyllotoxins are highly effective anticancer agents, but can cause a delayed toxicity: treatment-related acute myeloid leukemia or myelodysplastic syndrome (t-ML) (PMID: 18509329; 1944468; 2822173).

Drug-induced formation of MLL fusion genes has been associated with the development of t-ML (PMID: 8260707). Even though etoposide inhibits both topo II alpha and beta, the anti-tumor activity of etoposide is shown to be delivered primarily through inhibition of topo II alpha (PMID: 11531262) whilst the carcinogenic effect has been attributed to the beta isoform (PMID: 17578914). Recently, 64 genetic variants that contribute to etoposide-induced cytotoxicity were identified through a whole-genome association study (PMID: 17537913).

Tamoxifen

Tamoxifen, a selective estrogen receptor modulator (SERMs), is important for the treatment and prevention of breast cancer. Tamoxifen is extensively metabolized predominantly by the cytochrome P450 (CYP) system to several primary and secondary metabolites. Some of these metabolites exhibit more antiestrogenic effect in breast cancer cells than tamoxifen itself. The pathway depicts major pathways of tamoxifen metabolism that might have relevance to tamoxifen activity. Tamoxifen 4-hydroxylation is the most studied because it has been shown that 4-hydroxy-tamoxifen is approximately 30- to 100-fold more potent antiestrogen than tamoxifen.

Tamoxifen 4-hydroxylation is catalyzed by CYP2D6 and other isoforms.  The major metabolic pathway of tamoxifen is N-demethylation to N-desmethyltamoxifen. This pathway is primarly catalyzed by CYP3A4 and CYP3A5. N-Desmethyltamoxifen is further oxidized to a number of metabolites that appear important to tamoxifen activity. First, N-desmethyltamoxifen is hydroxylated by the CYP2D6 enzyme to endoxifen. This metabolite is as potent as 4-hydroxytamoxifen in terms of antiestrogenic activity, while its plasma oncentrations in breast cancer patients is much higher than that of 4-hydroxytamoxifen. Second, N-desmethyltamoxifen undergoes sequential metabolism to metabolite E, which exhibit in vitro estrogenic activity. Anthracyclins Anthracyclines play an important role in the treatment of cancer, and doxorubicin was one of the first anthraycyclines isolated from Streptomyces peucetius. Doxorubicin is an essential part of treatment for breast cancer, childhood solid tumors, soft tissue sarcomas and aggressive lymphomas.

However, tumor cells quickly develop resistance to these drugs and healthy cells become toxic, the main toxic effect is cardiac failure. Doxorubicin is a cell cycle-specific drug that slows or stops the growth of cancer cells by inhibiting DNA synthesis in S phase. Its exact mechanism of antineoplastic activity is still unknown but may involve binding to DNA by intercalation between base pairs and inhibition of DNA and RNA synthesis. Taxol (paclitaxel) Harris et al. [64] have studied the metabolism of taxol in human hepatic microsomes.

Their findings suggest that CYP3A4 is the major catalyst of the formation of a minor metabolite of taxol, whereas the identity of the enzyme(s) responsible for 6-ac-hydroxytaxol formation could not be assigned with certainty. 6-ac-hydroxytaxol is the major, but inactive metabolite of this antitumour drug in humans. The results of Kumar et al. suggested that taxol 6-a-hydroxylation in human liver is mediated by CYP3A, but apparently not CYP3A4. Cresteil et al. , however, reported that 6-a- hydroxytaxol formation can be assigned to the CYP2C subfamily, a finding later confirmed by Rahman et al..

These investigators showed that, of several human P450 enzymes studied, only CYP2C8 formed detectable 6-a-hydroxytaxol. There was no interaction between doxorubicin and taxol. However, interactions resulting from induction or inhibition of P450 enzymes, especially CYP3A4 and CYP2C8, can be anticipated to occur in clinical practice. More studies about the effects of other drugs on taxol pharmacokinetics are awaited.  Docetaxel belongs to the class of taxane antineoplastic agents that act by inducing microtubular stability and disrupting the dynamics of the microtubular network.

The drug has shown a broad spectrum of antitumour activity in preclinical models as well as clinically, with responses observed in various disease types, including advanced breast cancer and non-small cell lung cancer. The pharmacokinetics and metabolism of docetaxel are extremely complex and have been the subject of intensive investigation in recent years. Docetaxel is subject to extensive metabolic conversion by the cytochrome P450 (CYP) 3A isoenzymes, which results in several pharmacologically inactive oxidation products.

Elimination routes of docetaxel are also dependent on the presence of drug-transporting proteins, notably P-glycoprotein, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, impact substantially on interindividual variability in drug handling. Strategies to individualise docetaxel administration schedules based on phenotypic or genotype-dependent differences in CYP3A expression are underway and may ultimately lead to more selective chemotherapeutic use of this agent. Medroxyprogesterone acetate (MPA)

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced or recurrent breast cancer and endometrial cancer. The drug is extensively metabolized in the intestinal mucosa and in the liver. Cytochrome P450s (CYPs) involved in the metabolism of MPA were identified by using human liver microsomes and recombinant human CYPs. Methadone and Antibiotics Methadone is subject to dangerous drug interactions at CYP3A4. Methadone is largely metabolized in the liver by CYP3A4 to the N-demethylated derivative EDDP (2- ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine).

CYP3A4 activity varies considerably between individuals, and this variability is responsible for the large differences in methadone clearance and doses needed for pain relief. Patients on methadone who are also on certain psychotropic drugs, antibiotics, antifungal, macrolides, anticonvulsants or antiretroviral drugs have a significant risk for pharmacokinetic interactions leading to opioid toxicity or withdrawal. Ciprofloxacin is commonly used for infections in cancer and is a potent inhibitor to CYP1A2, CYP2D6, and CYP3A4.

Profound sedation is reported with the combination of methadone and ciprofloxacin. Caution should be taken whenever ciprofloxacin is added to steady doses of methadone. CYP3A4 Inhibitor Antifungal medications Triazoles are used widely in cancer and palliative medicine to treat fungal infections and are potent inhibitors of CYP3A4. Itraconazole is the most potent inhibitor of commonly used triazole. Fluconazole at high doses has the same inhibition as itraconazole. Ketoconazole has the lowest Ki and the greatest inhibition of azoles but is less important because it is infrequently used.

Azole antifungals delay the clearance of certain benzodiazepines (diazepam, alprazolam, and midazolam), methadone, and fentanyl. Terbinafine has no significant CYP3A4 interactions and is preferred as an oral antifungal if patients are on CYP3A4 substrates. Discussion In adults, CYP3A4 and CYP3A5 are the most important among the four CYP3A subfamily members for CYP3A-mediated drug metabolism, and because of the genetic diversity in the genes encoding these proteins, genotyping for CYP3A4 and CYP3A5 variants may be useful for prediction of total hepatic CYP3A activity.

Genetic differences may also explain 60 to 90% of the observed variation in CYP3A4-mediated drug- metabolizing capacity between patients. Over 30 single nucleotide polymorphisms in CYP3A4 have been published, representing alleles CYP3A4*1 to CYP3A4*19, most of which are very rare and unlikely to impact on CYP3A4 activity in vivo. The best characterized variant, a promoter variant with an A to G transition at nucleotide 392 (CYP3A4*1B), was shown in vitro to have increased transcriptional activity.

A recent study showed a dose-dependent association between CYP3A5*3C genotype and plasma concentrations of ABT-773, where drug exposure was higher in probes midazolam, erythromycin, and nifedipine. One recent study involving a predominantly white population of 67 cancer patients observed 1. 7-fold higher midazolam clearance in 9 patients with the *1/*3 genotype at the CYP3A5*3C allele compared with 58 patients with the *3/*3 genotype. These data are not consistent with the present CYP3A5-negative individuals (those that were homozygous variant [*3/*3 genotype]) only at the highest dose administered (450 versus 150 or 300 mg).

When CYP3A4 drug- metabolizing capability has become saturated, individuals that express CYP3A5 may metabolize the compound more quickly because of the additional activity of a second major CYP3A enzyme. The present study confirms the association between CYP3A4*1B and prostate cancer occurrence and severity. A novel aspect of this report is that CYP3A43 is also associated with prostate cancer, particularly in the context of family history-positive disease. CYP3A4 is expressed preferentially in the prostate and is involved in testosterone metabolism. CYP3A43 is alternatively spliced and can create mRNA hybrids with CYP3A4.

This evidence for a biological interaction between CYP3A4 and CYP3A43, in addition to their overlapping substrate specificity for testosterone is of potential relevance to the observation made here of interactions between CYP3A4 and CYP3A43. In general, the results showing disease associations with CYP3A4 and CYP3A43 are consistent with knowledge of gene and allele function in these genes as declared by several researches. CYP3A4 and CYP3A43 are involved in the metabolic deactivation (hydroxylation) of testosterone. CYP3A43 is preferentially expressed in the prostate. However, the function of CYP3A4*1B has been controversial.

In addition to epidemiologic evidence that CYP3A4*1B is associated with prostate cancer, the basic science literature has not consistently supported a functionally significant effect. A number of authors have studied the relationship of CYP3A4 expression or function of CYP3A4*1B. Most of the authors concluded that no biologically meaningful effects existed given the small magnitude of effects that were observed. However, almost all studies have reported consistent eleva- tions in expression associated with CYP3A4*1B in the range of 20 –200% increase over the consensus CYP3A4*1A.

Finally, I also report significant differences in haplotype frequency distributions by race and case-control status. The observation that the combined CYP3A4-CYP3A5-CYP3A43 haplotype may contain additional information about risk prediction beyond that of CYP3A4 genotypes alone suggests that other genes in this region may also be involved in the etiology of prostate cancer or that the consideration of haplotypes in this region provides improved statistical information for studies evaluating prostate cancer risk and progression.

Further continuation of my study includes Xenobiotics, like anticancer drugs such as docetaxel, bind to steroid and xenobiotic receptor. Ligand-activated steroid and xenobiotic receptor forms heterodimer with retinoid X receptor and binds to the promoter region of the CYP3A4 gene and activates its transcription. Recent studies showed that coregulators, including silencing mediator for retinoid and thyroid receptor and steroid receptor coactivator-1, mediated basal and xenobiotic-induced transcriptional activity of CYP3A4.

The investigators found that the antifungal agent ketoconazole inhibited corticosterone-induced CYP3A4 transcriptional activity by interacting with these coregulators. Ritonavir may block docetaxel-induced expression of CYP3A4 by also affecting these coregulators. Further studies clearly will be needed to elucidate molecular mechanism by which ritonavir inhibits docetaxel-induced expression of CYP3A4. Moreover Interindividual variability in CYP3A4 expression is a major confounding factor for effective cancer treatment and methods to predict CYP3A4-mediated drug clearance may have clinical utility in this setting.

Although acute inflammation has long been recognised to repress drug metabolism, it is now becoming apparent that cancer patients exhibiting clinical and laboratory features of an inflammatory response have reduced expression of CYP3A4 and possibly other genes relevant to anticancer drug disposition. Cytochrome P450 3A4 (CYP3A4) is the major xenobiotic metabolizing enzyme in humans. A broad specificity coupled with high levels of expression in the liver means it is responsible for the metabolism of more than half of all prescribed drugs (Guengerich,1997).

When patients receive several medications concurrently, unwanted and life-threatening effects can result from the competition for the same drug-metabolizing enzyme affecting the blood levels of the competing drugs. Cancer patients would seem to be significantly at risk in this respect, because CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e. g. , analgesics) and side effects (e. g. , antiemetics and antidiarrheals) and to treat comorbidities.

The anti- cancer drugs metabolized by CYP3A4 include docetaxel (Marre et al. 1996), cyclophosphamide (Chang et al. , 1993), ifosfamide (Walker et al. , 1994), etoposide (Kawashiro et al. , 1998), tamoxifen (Crewe et al. , 1997), irinotecan (Santos et al. , 2000), vinblastine (Zhou-Pan et al. , 1993), and vinorelbine (Kajita et al. , 2000). Although there is a marked interindividual variation of pharmacokinetic parameters be-tween patients (Evans and Relling, 1999), and such variation in patient response is often attributed to polymorphism in P450 genes, CYP3A4 is an exception because only a small percentage of the variation in activity can be attributed to genotype (Lamba et al. 2002a,b). Interactions with comedicated compounds are therefore likely to be particularly important in explaining variations in anticancer drug pharmacokinetics and side effects. If a patient experiences significant toxicity during chemotherapy, the clinician will usually reduce the dose of the cytotoxic drug, reducing the anticancer effect. A more appropriate action might be to substitute a different comedication that will not interact with the therapy and so maintain dose intensity of the cytotoxic drug.

Thus, identifying potential drug-drug interactions involving CYP3A4 is important for improving the treatment of cancer. The development of methods to predict such interactions could lead to the administration of more effective, less toxic drug regimes. Hence the next objective relating the cancer study will comprise of

1. To review the relevance of CYP3A4 variability to drug metabolism in the setting of cancer and to understand how inflammation associated with malignancy contributes to both this variability and to adverse treatment outcomes.
2. To examine the relationship between tumour-induced inflammation and repression of CYP3A4 and to explore methods of dosing of anticancer drugs in the setting of advanced cancer. In conclusion, the present study confirms the association of CYP3A4*1B and prostate cancer occurrence and severity, suggests a role for CYP3A433 in prostate cancer etiology, and further elucidate the relationships of multiple genotypes and haplotypes at the CYP3A locus with prostate cancer etiology.

Combined with information about the function of these genes, there is growing evidence that one or more of the genes in the CYP3A locus are involved in prostate cancer etiology. The most important and best characterized enzyme of the CYP3A subfamily, CYP3A4, metabolizes many essential drugs. As discussed above, the CYP3A subfamily plays a role in the metabolism of several anticancer agents. It should, however, be emphasized that the metabolism of many essential anticancer agents remains poorly characterized (mainly due to analytical difficulties) and not all P450 enzymes participating in their metabolism have been identified.

Therefore, it is usually not known (with the possible exception of ifosfamide and taxol) to which extent CYP3A enzymes contribute to the overall metabolism of specific anticancer agents. However, the role of CYP3A4 may be crucial in many cases since it is the most abundant P450 enzyme in human liver and it is also inducible. Since many inhibitors and inducers of CYP3A are widely used in clinical practice, the potential for interactions between these agents and anticancer drugs is considerable.

Furthermore, if anticancer agents that are substrates for CYP3A are used together in combination chemotherapy, the efficacy and toxicity of one or more of the components (or any other concomitantly used CYP3A substrate) may increase as a result of competitive inhibition of metabolism. It should also be recognized that many anticancer agents have active metabolites which, depending on their potency and pharmacokinetics, may contribute to the clinical response.

Inhibition of the metabolism of the (active) parent drug might result in reduced production of an essential active metabolite, and the effects of the parent drug might not be enhanced as much as the increased plasma concentrations would suggest. Therefore, it is difficult to evaluate the clinical significance of pharmacokinetic interactions without pharmacodynamic data. In the light of the role of the CYP3A subfamily in the metabolism of several anticancer agents and the effects of P-glycoprotein inhibitors on their pharmacokinetics, appropriate caution should be exercised when combining other drugs with cancer chemotherapy.

Interestingly, many CYP3A4 substrates are P-glycoprotein inhibitors. More clinically important interactions between anticancer drugs and CYP3A inhibitors as well as P-glycoprotein inhibitors are likely to emerge, and further study is required in this field.

References

1. Charnita Zeigler-Johnson, Tara Friebel CYP3A4, CYP3A5, and CYP3A43 Genotypes and Haplotypes in the Etiology and Severity of Prostate Cancer
2. Gellner K, Eiselt R, Hustert E, et al. Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. . Sarah J. Plummer,2 David CYP3A4 and CYP3A5 Genotypes, Haplotypes, and Risk of Prostate Cancer.
3. Hamzeiy H, Bombail V, Plant N, Gibson G, Goldfarb P. Transcriptional regulation of cytochrome P4503A4 gene expression: effects of inherited mutations in the 5-clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.
4. J Natl Amirimani B, Ning B, Deitz AC, Weber BL, Kadlubar F, Rebbeck TR. Transcriptional activity effects of a CYP3A4 promoter variant.
5. Spurdle AB, Goodwin B, Hodgson E, et al.
6. The CYP3A41B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer.
7. Westlind A, Lofberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M. Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5-upstream regulatory region43.
8. Floyd MD, Gervasini G, Masica AL, et al. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Kari T. Kivisto, Heyo K. Kroemer & Michel Eichelbaum The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions
9. Channa Keshava, Erin C. McCanlies, and Ainsley Weston CYP3A4 Polymorphisms—Potential Risk Factors for Breast and Prostate Cancer: A HuGE Review
10. Abdo Haddad, Mellar Davis, Ruth Lagman The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions .
11. Baker, Sharyn D, Sparreboom, Alex, Verweij, Jaap Clinical Pharmacokinetics of Docetaxel: Recent Developments
12. . Jean-Didier Marechal, Jinglei Yu, Simon Brown, Iouri Kapelioukh, Elaine M. Rankin In-silico and In-vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer
13. Evans WE, Relling MV. Clinical pharmacokinetics-pharmacodynamics of anticancer drugs 15. www. pharmgkb. org/search/annotatedGene/cyp3a4/

• A) The hypothesis being tested here is the enhancement in the lipase activity of phospholipase C-?1 via phosphorylation of tyrosine 783.
• B) To perform the experiment equal concentrations of purified phospholipase-C-?1 were set on incubation with the active kinase domain of FGFR2 and ATP in bovine serum albumin containing buffer.

The samples of this reactions were tested for two activities:

for lipase activity in the phospholipid vehicles indicated in the figure on left y axis. Secondly the phosphate incorporation in phospholipase-C-?1 was studied, illustrated at right y axis of figure.This was performed to check the phosphorylation of tyrosine and auto inhibition of PLC-? isozymes, 775/783 of PLC-?1 were substitutes at the place of phenylalanine, they could be used individually or together, but in the experiment tyr783 is used individually.

Phospholipase activity of resulting mutant after purification was quantified with active domain of FGFR2K (helps in phosphorylation and activation of phospholipase). certain known moles of phosphates were added into purified PLC-?1 in wild type under above mentioned conditions and was observed that phospholipase activity was enhanced 10 times.

The mutation of tyr783 completely nullified the kinase stimulated acceleration of phospholipase activity along with reduction in FGFR2K-promoted phosphorylation of PLC-?1. Therefore, phosphorylation of Tyr783 is vital forrelief of auto-inhibition.

• C) Studies reveal that Tyr-783 was essential for auto inhibition.

As discussed above, permanent phosphorylation of tyr-783 will completely nullify the kinase stimulated and FGFR2K stimulated phosphorylation of PLC-?1. lipase activity of PLC-?1 will be enhanced across its limits and over-expression of PLC-?1 can induce malignant transformation.

The results could be leading to production of carcinoma cells. It has been found in various studies that activity of PLC-?1 is more in cancerous cells as compared to normal cells. So, permanent phosphorylation tyr783 could be a way leading to malignant cancers.

Breast malignant neoplastic disease occurs when chest cells grow abnormally and uncontrollably. It is the most common malignant neoplastic disease in the UK. This is indicated in the pie chart below where chest malignant neoplastic disease histories for the highest per centum happening among adult females, that is approximately 26 % . An estimated 46 000 adult females are diagnosed every twelvemonth. The two chief hazard factors for chest malignant neoplastic disease are gender – being a adult female and age – turning older. In fact 8 out of 10 of the diagnosed patients are adult females above 50 old ages old. 90 % of chest malignant neoplastic disease is caused by environmental factors while the staying 10 % is due to familial defect. Breast malignant neoplastic disease can be treated if it is detected at an early phase, doing the patients ‘ opportunities of endurance greater. Among the symptoms of chest malignant neoplastic disease are the presence of a ball or thickener in the chest tissue.

A Possible Solution – Mammogram

In my sentiment all adult females particularly those above the age of 50 and those with a strong household history of chest malignant neoplastic disease should travel for regular mammographic showing. A mammogram is really of import for chest malignant neoplastic disease showing and early sensing. It is an X-ray exposure of the chests where consequences are studied to observe any abnormalcies or locations of leery tissue. Harmonizing to the National Health Service ( NHS ) UK, 1 400 lives are saved because of testing.

There are a few differences between testing mammograms and other mammograms. Screening mammography is carried out when there is no ball or seeable marks of malignant neoplastic disease. However, if a specific ball demands to be looked at, so a diagnostic mammography is done. Here my research is based on testing mammography.

There is a important difference in sentiment sing how frequently adult females should travel for mammograms. The American Cancer Society ( ACS ) suggests that all adult females over 40 should travel for mammograms one time every twelvemonth while the National Cancer Institute ( NCI ) of the US advises adult females to travel every 1-2 old ages.  I agree with NCI as their suggestion would intend that adult females are non exposed to radiation excessively frequently. Increased exposure to radiation increases the hazard of acquiring malignant neoplastic disease.

A mammogram is conducted on an outpatient footing and stopping points for about 30 proceedingss.  During the process, a qualified radiotherapist intially places merely one chest on a little level home base that has an X-ray home base under it. Above the chest there is another level home base. The machine presses the chest down between the home bases keeping the chest in place and bettering the acuteness of the image. When the chest is compressed, there is a small uncomfortableness.  Small explosions of radiation, something like wireless moving ridges is produced by the tubings in the machine and is passed through the chests. The image formed is recorded on photographic movie or a particular digital image entering home base. The chest is less heavy in comparing to the tumour. Therefore the chest appears in grey sunglasses on the mammography while the tumour is white and the air is black as it is the least dense.

A radiotherapist will analyze the images and look out for any marks of malignant neoplastic disease. A signed study is sent to the physician who will explicate the consequences to the adult female.

When a adult female goes for this process, she is told non to have on any deodourant, pulverization or lotion in her axillas or her chest as these would look as calcium musca volitans on the mammogram.  Sometimes alternatively of tumours physicians may happen cysts, calcifications and fibroadenomas on the mammograms. Calcifications are non breast malignant neoplastic disease but can be an indicant of precancer. They are little measures of Ca that appear in the soft tissue of the chest. Fibroadenomas are benign tumours made of hempen and glandular chest tissue that are removed as a precautional measure. Cysts are benign unstable – filled pouch that are non related to malignant neoplastic disease.

Effectivenes

From the first graph, it is observed that the rate of early diagnosing of chest malignant neoplastic disease had significantly improved because of the addition in the figure of adult females who underwent mammography. Consequently, the rate of late diagnosing of chest malignant neoplastic disease decreased. The 2nd graph shows that when chest malignant neoplastic disease is detected early, there is a diminution in the mortality rate. [ 9 ] I strongly believe that naming chest malignant neoplastic disease early through mammography helps better adult females ‘s opportunities of endurance.

A by Reuters in Washington, US dated October 6th 2009 stated that a survey conducted by US research workers found that 75 % of adult females who died of chest malignant neoplastic disease ne’er had a mammogram, or were diagnosed after their first of all time mammogram.

Dr Blake Cady of Cambridge Hospital and Harvard Medical School in Massachusetts said:

“ Womans who are in testing programmes have merely a 4.7 % mortality. Womans who are non screened have a 56 % mortality. ”

To further turn out mammogram effectivity, below is a drumhead from a existent life chest malignant neoplastic disease subsister.

Pam ‘s narrative

‘Diagnosed at 46 with chest malignant neoplastic disease, after holding skipped her mammogram for a twosome of old ages, Pam ‘s intervention involved mastectomy, radiation and chemotherapy. She wants adult females to acquire an one-year mammogram, get downing at age 40, to catch malignant neoplastic disease early and avoid extended intervention like hers. ‘

Deductions

While carry oning this research, I encountered one societal issue that is, non all adult females realize the importance of acquiring a mammogram. This degree of consciousness varied due to different degrees of instruction among the adult females. The graph below supports my statement.

Percentage of US adult females aged 40 and older who Have Had a Mammogram in the last 2 old ages by Education Level

Based on the graph adult females with more than a college instruction are most likely to hold had a mammogram in the last 2 old ages compared to adult females with lower degrees of instruction.  I think these adult females are cognizant of this of import showing tool. I besides feel at that place should be more public wellness instruction because a deficiency of information can take to misinformation. For illustration, Indian adult females with chest malignant neoplastic disease have to utilize separate utensils because of the mistaken believe that the disease is contagious.

I would besides wish to turn to an economical issue referirng the usage of mammograms. The American Cancer Society suggests that adult females above 40 should acquire a mammogram every twelvemonth but many adult females are forced to jump their mammograms because they merely can non afford it. Research workers at Brown University in 2002, discovered mammograms bing US $ 400 is a challenge for many adult females.

Despite this, conditions in the US are still non every bit bad as in some underdeveloped states as seen in quotation mark below.

“ The United States spends about US $ 8.1 billion to name and handle chest malignant neoplastic disease, but in the metropolis of Poona, India, place to 3.5 million adult females, merely one medical installation provides comprehensive chest malignant neoplastic disease diagnostic and intervention services. ”

Besides, adult females populating in destitute states like Kenya feel incapacitated and merely wait to decease because they can non afford to travel abroad for intervention. It is expected that by 2020, 70 % of all chest malignant neoplastic disease instances will be in hapless states.  This is why I think authorities should seek to happen a manner to guarantee all adult females get their mammograms done.

Benefits and Risks of Mammography

A picture by ‘NHS picks ‘ entitled “ Having A Mammogram ” highlights the advantages of holding a mammography as it can observe abnormalcies which are 3-4 millimetres in size. These abnormalcies are impossible to experience if a individual were to analyze her ain chests.  Sometimes a mammogram is more accurate than other diagnostic process. A specific form of Ca sedimentations known to do chest malignant neoplastic disease can merely be seen clearly on a mammogram. [ 25 ] Having a mammography would non go forth any radiation in a patient ‘s organic structure. X raies usually have no side effects in the diagnostic scope. A tumour detected early is more likely to be cured.

Mammograms have certain defects nevertheless. Sometimes false-negatives can happen. This is when chest malignant neoplastic disease is present even though the mammograms appear normal. It happens largely in immature adult females because they have denser chests compared to older adult females whose chests are more fatty devising tumours easy seeable on mammograms.

At the same clip, false-positives besides occur because radiotherapists erroneously decide the mammograms are unnatural when really there is no malignant neoplastic disease nowadays. This causes unneeded anxiousness and emphasis for the adult female. To avoid false-positives, an ultrasound and a biopsy is conducted.

The doses of X ray in mammograms is really little but when it is done repeatedly it is harmful and can increase the hazard of acquiring malignant neoplastic disease.

Alternate Solutions

An article titled New ‘Breast Pap Smear ‘ was written by Duke Medicine News and Communications. This trial is presently undergoing three clinical tests countrywide in the US. It works by utilizing a really narrow acerate leaf to take cells from subdivisions of the whole chest. The quotation mark below farther explains the trial.

Dr Victoria Seewaldt, a scientist and chest oncologist at the Duke Comprehensive Cancer Center said:

“ Merely as we do with a cervical pablum vilification, we can now study cells from the whole chest, analyze them under the microscope and trial for early alterations that frequently precede breast malignant neoplastic disease. Then we can give adult females a preventative agent to see if we can eliminate her unnatural cells and therefore prevent malignant neoplastic disease from developing. ”

A specific cistron known as RAR beta controls how breast cells use vitamin A to guarantee their good wellness. Research done has shown that the cistrons in chest malignant neoplastic disease patients lose its ability to map. This ‘pap vilification ‘ trial can observe the presence or absence of this cistron. Without it, the possibility of developing malignant neoplastic disease is higher. Hence RAR beta Acts of the Apostles as a molecular marker to find the oncoming of malignant neoplastic disease.

I strongly believe that the new chest ‘pap vilification ‘ is an first-class discovery in the battle against chest malignant neoplastic disease. Once the clinical tests are deemed successful, this should be carried out on all adult females.

Ultrasound Imaging

Ultrasound Imaging, besides known as Ultrasound Scanning provides images of the internal constructions of the chests. During an ultrasound, a doctor may utilize Doppler Techniques to measure the blood flow or deficiency of blood flow in a chest mass. At times it is possible to find the cause of the mass. Doppler ultrasound is a technique used to measure blood flow through a blood vas.

Breast ultrasound maps to assist name breast abnormalcies detected during a physical scrutiny and to qualify possible abnormalcies seen on a mammogram. A chest lesion detected and classified sometimes can non be interpreted adequately through mammography entirely. An ultrasound can besides distinguish if an abnormalcy is solid or fluid-filled ( benign cyst ) or both solid and cystic. A solid may be a benign or malignant tumour. Ultrasounds show extra characteristics of the unusual countries on the chest.

Beginning Evaluation

In my sentiment, the ‘National Health Service Choices UK ‘ web site ( nhs.uk/Conditions/Cancer-of-the-breast-female ) is really comprehensive and factual. This beginning aims to give nonsubjective information and counsel to the populace on chest malignant neoplastic disease. It is approved by a clinical expert and is funded by the Department of Health. It has been certified as a dependable wellness and societal attention information beginning by The Information Standard and has to run into certain editorial policies. So I think this is a reputable beginning. I retrieved information on the importance of holding a mammogram for early diagnosing of chest malignant neoplastic disease as stated on page 9. The undermentioned two web sites ; besides provided the same information.

An article from the Time magazine entitled The Changing Face Of Breast Cancer, volume 170 published in October 2007 is another dependable beginning. I believe this article was good researched because it has included positions from adult females across the universe. This article gives facts and figures supported by other beginnings. For illustration, the quotation mark on page 8 by Masilamany J, from the Sun newspaper can be found in this article. Besides, the information that chest malignant neoplastic disease is the most common disease among adult females is besides found in.

In the beginning, cyclin-dependent kinase 1 CDK1 for example, is a cell division cycle protein homolog 2, regarding a research paper that explains the role of CDK1 in the human breast cancer cells. They found that CDK1 rather than any types of CDK is fatal to the mutated version of MYC- dependent cancer that leads to a depletion of the oncogene in human cancer cells.

The study reveals that the reason for the MYC breast cancer cells duplation is targeting CDF1 exhibit any other CDK cell lines. The primary purpose was to figure out the mechanism of CDK1 inhibition which controls and target the breast cancer cells in human and both phosphorylation and expression of MYC during the cell cycle process.

To confirm that, they used siRNA knockdown to measure the expression level of MYC. Further, other than any mutants, apoptosis leading to the uncontrolled cell proliferation especially in human breast cancer disease that was measured by the detection of caspase-cleaved cytokeratin 18 using flow cytometry technique.

The controls that were used are estrogen receptor ER-positive and ER-negative, they found increased at the number of the protein activity for the positive and the negative correlation, but the gene expression was high at the positive one and decreased to zero at the negative control (that means no reaction between them).

They confirmed that CDK1 is essential for cell division and necessary for driving the cell cycle in all cell types.To initiate intracellular signaling pathways and stimulate the cell cycle entry, mitogens substance bind to the cell surface receptor with the activation form of GTPase Ras that activates MAP kinase cascade. That will lead to the expression of encoding gene of the transcription regulatory protein like MYC.

Moreover, MYC will increase the expression of many late response genes, including some genes that lead to increased G1-CDK activity (cyclin D Cdk4), which triggers the phosphorylation of members of the tumor suppressor protein (Retinoblastoma protein) family. The inactive form of RB proteins can release the E2F target genes to initiate the transcription process in G1 and S phases, to enhance the G1- CDK and S- CDK activities and the phosphorylation of RB proteins forming a positive feedback loop.