|Year : 2012 | Volume
| Issue : 1 | Page : 40-45
CYP 2D6 polymorphism: A predictor of susceptibility and response to chemoradiotherapy in head and neck cancer
Pragya Shukla1, Deepak Gupta1, Mohan Chand Pant2, Devendra Parmar3
1 Department of Radiation Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
2 Department of Radiation Oncology, Chattrapatti Shahuji Maharaj Medical University, Lucknow, India
3 Developmental Toxicology Division, Indian Institute of Toxicology Research (Formerly: Industrial Toxicology Research Centre), Council CSIR, Lucknow, India
|Date of Web Publication||19-Apr-2012|
Department of Radiation Oncology, Tata Memorial Centre, Mumbai
Aims: A major problem in cancer pharmacology is the unpredictability of the outcome of therapy, both in terms of tumor response and host toxicity. Pharmacogenetic variability associated with the drug metabolizing enzyme systems is a major determinant of variations in these outcomes.
Materials and Methods: A case-control study of 100 male cases of head and neck squamous cell carcinoma and equal number of healthy controls was conducted. Genomic DNA isolated from blood samples collected from controls and patients was studied by PCR-RFLP technique for CYP2D6 polymorphism. All patients received three cycles of cisplatinum-based sequential chemoradiotherapy.
Results: The increased frequency of variant genotypes was associated with a statistically significant increase in the risk in the cases both in CYP2D6*4 and *10. The effect of interaction of the risk modifiers such as cigarette smoking or tobacco chewing or alcohol drinking with the CYP2D6 genotypes in the controls and patients was found to be significant. Response to therapy in patients with variant genotypes of CYP2D6 (CYP2D6*4 and CYP2D6*10) and treated with radio and chemotherapy regimen was poor.
Conclusions: Functional enzyme deficiencies due to polymorphism in CYPs are not only important in enhancing susceptibility to head and neck squamous cell carcinoma but also in determining chemotherapeutic response.
Keywords: CYP2D6, head and neck cancer, polymorphism, responders, tobacco
|How to cite this article:|
Shukla P, Gupta D, Pant MC, Parmar D. CYP 2D6 polymorphism: A predictor of susceptibility and response to chemoradiotherapy in head and neck cancer. J Can Res Ther 2012;8:40-5
|How to cite this URL:|
Shukla P, Gupta D, Pant MC, Parmar D. CYP 2D6 polymorphism: A predictor of susceptibility and response to chemoradiotherapy in head and neck cancer. J Can Res Ther [serial online] 2012 [cited 2013 Jun 19];8:40-5. Available from: http://www.cancerjournal.net/text.asp?2012/8/1/40/95172
| > Introduction|| |
With an estimated global annual incidence and mortality rates of 650000 and 350000 respectively, head and neck cancer is the sixth most common type of cancer, representing about 6% of all cases with alcohol and tobacco being recognized as the major etiological factors.  Though from the 1960s through the 1980s, surgery and radiation therapy (RT), often postoperative have remained the primary modalities used to treat these tumors, meta-analysis and randomized controlled trials have established the role of chemoradiation as the standard of care in head and neck cancer management. 
A major problem in cancer pharmacology is the unpredictability of the outcome of therapy, both in terms of tumor response and host toxicity. , Cytochrome P450 (CYP450) enzymes which are essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A2 are also necessary for the detoxification of foreign chemicals and the metabolism of drugs.  Though there are more than 50 CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90% of drugs. , CYP2D6 is the most important polymorphic enzyme active in the metabolism of drugs. This is the only CYP which is not inducible and therefore genetic variation contributes largely to the interindividual variation in the enzyme activity.  Polymorphism occurs when a variant allele replaces one or both wild type alleles. Variant alleles usually encode enzyme that has reduced or no activity. Pharmacogenetic variability associated with this drug metabolizing enzyme system is a major determinant of variations in the outcomes.
Genetic factors thus in addition to playing an important role in determining susceptibility and predisposition to HNSCC may also influence the drug metabolism thus influencing the response achieved. The present study aimed to explore into gene-environment interaction, with respect to pathogenesis of head and neck tumor and also tried to establish an association between genetic polymorphism and treatment response.
| > Materials and Methods|| |
The study group comprised of cytologically or histologically proven and previously untreated 100 male cases with head and neck squamous cell carcinoma of the oral cavity, oropharynx, the hypopharynx, and the larynx and an equal number of healthy controls. All the cases and the controls included in the study belonged to the same ethnic group (Indo-European community) of North India based on geographical location and linguistic basis. Controls were frequency-matched to cases by year of birth in 15-year classes.
Informed consent of the cases was obtained before inclusion in the study. The study was approved by the institutional ethics committee. Information pertaining to dietary habits, family history of disease, smoking, tobacco chewing and alcohol drinking was obtained in the questionnaire filled by the cases as well as the controls. Individuals having regular smoking habits and smoking index (cigarettes/day ×365 days) of 730 or more were classified as smokers. Likewise, smokeless tobacco dose was estimated as 'chewing year' (i.e. CY= frequency of tobacco chewed or kept/day × duration of year). Those who had CY of 365 or more were considered as tobacco chewers. Similarly cumulative exposure of alcohol drinking was derived by multiplying the total yearly consumption of alcohol (in L/year) by the duration of habitual alcohol drinking (in years). Those who had cumulative exposure of alcohol about 90 L were considered as regular alcohol users in our study.
All patients included in the study had a Karnofsky performance status of at least 70 and adequate bone marrow reserve, normal hematological parameters, normal liver and renal functions. Subjects with any concurrent illness who defaulted during the treatment and whose expected survival was not more than 6 months were excluded from the study.
The patients were staged according to TNM staging (American Joint Committee Classification 2002). Response was categorized as complete response, partial response or no response based on WHO response assessment criteria. Genomic DNA was isolated from blood samples collected from controls and patients. CYP2D6 polymorphism in genomic DNA was studied by PCR-RFLP technique.
Patients were subjected to five-seven cycles of concurrent chemotherapy with radiotherapy. Each cycle included administration of 35 mg/m 2 of cisplatin once every week for seven weeks along with 70 Gy of radiation @ 200cGy/#, 5# per week for seven weeks.
| > Results|| |
A total of 200 individuals, i.e. 100 patients suffering from squamous cell carcinoma of head and neck and 100 age matched healthy controls, were genotyped for CYP2D6*4 and CYP2D6*10 polymorphism. Amongst the cases, 48% were found to be smokers whereas only 24% in the controls had smoking habit. Likewise, 37% of the cases and 23% of the controls were found to have the habit of chewing tobacco on daily basis. About 36% of the cases were reported to be alcohol drinkers based on the daily consumption of alcohol, as compared to 24% found amongst the controls. Cigarette smoking, tobacco chewing and daily alcohol use were found to be more prevalent in the patients when compared to the controls [Table 1]. The genotypic frequency of both the polymorphisms of CYP2D6 (CYP2D6 *4 and CYP2D6*10) in controls and patients is summarized in [Table 2] and [Table 3]. The number of individuals with heterozygous genotype of CYP2D6*4 was found to be slightly higher in the patients (44%) than the controls (28%). The increase in the frequency of heterozygous genotype was associated with a statistically significant increase in the risk (OR: 2.024; 95% CI: 1.12 to 3.64) in the cases. Similarly, an increase in the frequency of the homozygous mutant genotype of CYP2D6*4 was observed in the patients (7%) when compared to the controls (3%), which resulted in an increase in the crude odds ratio (OR: 2.487; 95% CI: 0.62 to 9.91) for homozygous mutant genotype. This increase in risk was not found to be statistically significant [Table 2].
|Table 1: Distribution of demographic variables and putative risk factors|
Click here to view
As evident from [Table 3], prevalence of poor metabolizers of CYP2D6*10 was also higher in patients, compared to the controls. The number of the individuals with homozygous variant genotype (CYP2D6*10) was significantly higher in the cases (23%) when compared to the controls (12%) (OR=2.215;CI=1.034 to 4.75). The increase in the frequency of heterogenous genotype of CYP2D6*10 resulted in an increase in the crude odds ratio (OR:2.2437, 95% CI: 1.145 to 4.395) which was found to be statistically significant [Table 3].
The effect of interaction of the risk modifiers such as cigarette smoking or tobacco chewing or alcohol drinking with the CYP2D6 genotypes in the controls and patients is summarized in [Table 4]. The number of individuals with variant genotypes (heterozygous and homozygous) of CYP2D6*4 was significantly increased in cases (73%) who were regular tobacco chewers as compared to the tobacco chewing controls (35%). This increase in the frequency of cases with variant genotypes of CYP2D6*4 resulted in several fold increase in the risk (OR: 5.0625, 95% CI: 1.6547 to 15.57) amongst the tobacco chewing cases which was found to be statistically significant. As observed with CYP2D6*4, the frequency of individuals who were regular tobacco chewers and carried variant genotypes of CYP2D6*10 was also significantly increased in the cases (76%) when compared to the controls (44%). This increase in the frequency of cases who were tobacco chewers resulted in an increase in the risk (OR: 4.0444, 95% CI:1.32 to 12.34) when compared to the tobacco chewing controls. Tobacco chewing was further found to be an important risk factor as reflected by an increase in the risk in the cases amongst tobacco-chewers when compared to the cases who were non-tobacco chewers [Table 4]. Cigarette smoking also increased the risk in the patients with CYP2D6 polymorphism when compared to the smokers in the controls [Table 4]. The number of individuals who were regular smokers and carried variant (heterozygous and homozygous) genotypes of CYP2D6*4 was significantly increased in the cases (63%) when compared to the controls (29%). The risk associated with cigarette smoking increased several fold in the patients with the variant genotypes of CYP2D6*4 (OR: 4.0476; 95% CI: 1.4072 to 11.6424) which was further found to be statistically significant. As observed with CYP2D6*4, the number of cases with variant genotypes of CYP2D6*10 was also increased amongst smokers which was associated with a significant increase in the risk (OR: 3.80; 95% CI: 1.3 to 10.98) compared to the smokers in controls [Table 4]. Our data further showed that number of the individuals with variant genotypes of CYP2D6*4 and who were regular alcohol users were significantly increased in the cases (67%) when compared to the controls (37.5%). The increase in frequency was associated with an increase in the risk (OR: 3.33;95% CI: 1.33 to 9.8) in the cases when compared to the controls, who were regular alcohol drinkers. Further, this increase in risk was found to be statistically significant [Table 4]. A significant increase in the risk was also observed in cases amongst the alcohol users (OR 5.2, 95% CI 1.698 to 15.92) with variant genotypes of CYP2D6*10 when compared to the alcohol users in the controls [Table 4]. No significant increase in the risk was observed in the patients amongst non-smokers or non-tobacco chewers or non-alcohol users and who carried variant genotypes of CYP2D6*4 or CYP2D6*10 polymorphism when compared to the respective controls [Table 4]. Like tobacco use, alcohol also appeared to be an important risk factor when the cases who regularly used alcohol and carried variant genotypes of CYP2D6 were compared with cases with similar genotypes but not using alcohol [Table 4]. An increase in the risk was observed in the cases with variant genotypes of CYP2D6*4 and *10 who were regular alcohol users when compared to cases with similar genotype but were not regular alcohol users.
|Table 4: Interaction between CYP2D6 genotypes and smoking, tobacco chewing and alcohol consumption and risk of squamous cell carcinoma of head and neck|
Click here to view
A follow-up study was also carried out in patients to study the effect of treatment on the patients with poor metabolizer or extensive metabolizer genotypes of CYP2D6 [Table 5]. Amongst the patients with wild-type genotype of CYP2D6(CYP2D6*1), 80% responded to the treatment of chemo and radio-therapy (responders) while 20% were non-responders. Majority of the patients with CYP2D6*4 genotype were found to be non-responders (73%), while only 27% exhibited good response (responders). This was a statistically significant difference. Likewise, amongst the poor metabolizers with CYP2D6*10 genotype, 47% responded to the treatment. This was again found to be statistically significant.
|Table 5: Treatment responses in patients of squamous cell carcinoma of head and neck with different CYP 2D6 genotypes|
Click here to view
| > Discussion|| |
Cytochrome P450 enzymes (CYP) play a central role in the metabolism of many drugs, chemicals and carcinogens. Differences in the activity of these enzymes are being held responsible for the interindividual variability in susceptibility toward chemical-induced carcinogenesis as well as drug response and toxicity.
There are more than 50 CYP450 enzymes, with a specific gene encoding each CYP450 enzyme. Every person inherits one genetic allele from each parent. Alleles are referred to as "wild type" or "variant". Wild type occurs most commonly in the general population. An "extensive" (i.e., normal) metabolizer has received two copies of wild type alleles. Polymorphism occurs when a variant allele replaces one or both wild type alleles. Variant alleles usually encode a CYP450 enzyme that has reduced or no activity.  Persons with two copies of variant alleles are known as "poor" metabolizers, whereas those with one wild-type and one variant allele have reduced enzyme activity. Persons inheriting multiple copies of wild-type alleles, which results in excess enzyme activity, are known as "ultrarapid" metabolizer. 
CYP2D6 gene, a highly polymorphic gene, has more than 70 allelic variants described so far. Deficiency of CYP2D6 is inherited as an autosomal recessive trait. Interethnic differences have been reported with this polymorphism being present in >50% of Chinese population and almost absent among Caucasians.  The present work establishes the presence of CYP2D6*4 and CYP2D6*10 polymorphism in North Indian population. The prevalence of the PM phenotype is slightly higher among Asians in the Indian subcontinent than in the Asian populations of southeastern and eastern Asia, with reported frequencies of 1.8-4.8%.  CYP2D6*10 may be present in as much as 50% of Asians and is responsible for diminished enzyme activity in IMs.  The percentage of PM in our population group is equal to 3% in 2D6*4 and 12% in 2D6*10 in the controls. However, the percentage of IM is 28% in 2D6*4 and 17% in 2D6*10 in the controls.
The higher prevalence of variant genotypes of both CYP2D6*4 and CYP2D6*10 in the cases has clearly shown the increased susceptibility of such cases to HNSCC. CYP2D6 variants have been earlier reported to be associated with increased susceptibility to breast carcinoma, bladder carcinoma, pituitary adenoma and also laryngeal carcinoma. ,,, Poor metabolizers of CYPs were also reported to be associated with lung cancer and laryngeal squamous cell carcinoma and other forms of cancers induced by PAHs. ,, Several fold increased risk in cases with variant genotypes of CYP2D6 and those using tobacco (chewers or smokers) have suggested the possibility of interaction of CYP2D6 genotypes with these risk factors. It has also been reported to influence the detoxification of the carcinogens such as the nitrosamine 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanone and polycyclic aromatic hydrocarbons (PAHs), which appears in tobacco smoke. A statistically significant increase in risk in tobacco chewing or cigarette smoking cases with variant genotypes of CYP2D6 could be possibly attributed to the lower ability of poor metabolizers for detoxifying the carcinogens generated by tobacco chewing or smoking. Poor metabolizers of CYP2D6 may have a higher carcinogen level and potent cell toxicity due to their impaired ability to detoxify the carcinogens. , Poor metabolizers of CYP2D6 are reported to have a significantly higher incidence of prostatic cancer in North Indian population compared with homozygous and heterozygous extensive metabolizers suggesting that the risk due to CYP2D6 poor metabolizer genotype could be attributed to the lesser detoxification capacity of the carcinogens.  Likewise, several fold increase in the risk in alcohol drinking cases with variant genotypes of CYP2D6 have suggested that alcohol possibly interacts with CYP2D6 genotypes in increasing risk. Though no data is available on interaction of CYP2D6 genotypes and alcohol, CYP2D6 is known to metabolize PAH found in hard liquors (eg whiskey), and N-nitrosoamines have been identified in beers.  Even though statistically significant increase in the risk was observed in alcohol drinking cases with CYP2D6 genotypes, the confounding of the effects by tobacco chewing or smoking cannot be ruled out. It is well established that alcohol act synergistically with tobacco to promote carcinogenesis in the head and neck by acting as a solvent for the penetration of various carcinogens through the mucosa of upper aero digestive organs. The relative risk among tobacco and alcohol abusers was found to be several times higher than non-smokers and non-drinkers.
Our study has further provided evidence that the treatment response in the patients with variant genotypes of CYP2D6 (CYP2D6*4 and CYP2D6*10) and treated with radio and chemotherapy regimen was poor as judged clinically. Drug metabolism is carried out primarily by families 1, 2, and 3.  Though CYP2D6 is a major enzyme which is known to catalyze the oxidation of about 30 important drugs, there have been no studies correlating treatment response of CYP2D6 with the use of cisplatinum-based chemotherapy. A possible explanation to the obtained poor response in patients with variant genotype is the concept of "overlapping substrate specificity". By this, we imply that as CYP2D6 belongs to the same family as CYP 2C19, there can be an overlap of their substrates thus a particular drug substrate may be metabolized by more than one isozyme.  The association of variant gene in CYP 2C 19 and poor response to treatment with cisplatinum has been documented.  It has been reported that a decrease in CYP2C19 activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs used in standard oncology.  Poor metabolizers of CYP2C19 were reported to exhibit little response to the respective chemotherapy than the normal genotype. 
Further, it has been found that platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of DNA repair genes are associated with differential DNA repair activity and may explain interindividual differences in overall survival after therapy with platinum agents. , However, the effect on clinical outcome can be difficult to predict based on the level of DNA repair. As an example, impaired DNA repair capacity may increase carcinogenesis and lead to more biologically aggressive tumors and decreased survival; on the other hand, decreased DNA repair may contribute to the persistence of functional platinum-DNA adducts that confer antitumor activity and impart more favorable prognosis. The association of single nucleotide polymorphisms in the genes involved in nucleotide excision repair (NER)/base excision repair (BER) with response to cisplatin-based chemotherapy has been studied in detail.  Gurubhagavatula et al in their study, concluded that the polymorphism in XRCC1 and XPD312 in lung cancer patients treated with platinum-based doublets resulted in poorer survival than those carrying wild-type genotypes.  It was also reported that the ERCC1C8092A variant was associated with a poor clinical outcome in lung cancer patients treated with platinum-based combinations.  Isla et al, reported that non-small cell lung cancer patients with wild-type Excision-repair cross-complementing 1 (ERCC1) genotype had a significantly longer survival than those carrying non-wild-type ERCC1.  Though the role of CYP2D6 in the metabolism of cisplatin is not yet reported, our data indicating poor response of chemotherapy in poor metabolizers suggests decreased efficacy of the drugs used in the chemotherapy in these patients.
A several fold increase in the risk to head and neck cancer in the cases with variant genotypes (poor metabolizers) and who were tobacco or alcohol users have further indicated the importance of gene-environment interactions in determining susceptibility to cancer. Likewise, poor treatment response of chemotherapy in patients with variant genotypes of CYP2D6 has further demonstrated that functional enzyme deficiencies due to polymorphism in CYPs are not only important in enhancing susceptibility but also in determining chemotherapeutic response. The current practice of dosage of chemotherapeutic drugs on the basis of height and body surface area may be imprecise. A more individualized approach using therapeutic drug monitoring, adaptive control regimens derived from pharmacogenetics offers a new and exciting alternative dosing approach.
This study brings forth the importance of developing more accurate measures of exposure at the DNA level of various environmental toxicants. The possibility of using genetic polymorphism as a biomarker for risk of development of carcinoma needs to be explored. The correlation of genetic analysis and drug metabolism for predicting treatment response needs to be studied further.
| > References|| |
|1.||Do KA, Johnson MM, Doherty DA, Lee JJ, Wu XF, Dong Q, et al. Second primary tumors in patients with upper aerodigestive tract cancers: Joint effects of smoking and alcohol (United States). Cancer Causes Control 2003;14:131-8. |
|2.||Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8. |
|3.||Calabrese EJ. Biochemical individuality: The next generation. Regul Toxicol Pharmacol 1996;24:S58-67. |
|4.||Chabot GG. Factors involved in clinical pharmacology variability in oncology (review). Anticancer Res 1994;14:2269-72. |
|5.||Guengerich FP. Characterization of human cytochrome P450 enzyme. FASEB J 1992;6:745-8. |
|6.||Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-21. |
|7.||Slaughter RL, Edwards DJ. Recent advances: The cytochrome P450 enzymes. Ann Pharmacother 1995;29:619-24. |
|8.||Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007;116:496-526. |
|9.||Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. JAMA 2001;286:2270-9. |
|10.||Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjöqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese CYP2D locus. Characterization of variant CYP2D6 genes present in subjects with diminished capability for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-9. |
|11.||Bernard S, Neville KA, Nguyen AT, Flockhart DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: Clinical implications. Oncologist 2006;11:126-35. |
|12.||Ladona MG, Abildúa RE, Ladero JM, Román JM, Plaza MA, Agúndez JA, et al. CYP 2D6 genotypes in Spanish women with breast cancer. Cancer Lett 1996;99:23-8. |
|13.||Gomes L, Lemos MC, Paiva I, Ribeiro C, Carvalheiro M, Regateiro FJ. CYP 2D6 genetic polymorphisms are associated with susceptibility to pituitary tumors. Acta Med Port 2005;18:339-44. |
|14.||Gajecka M, Rydzanicz M, Jaskula-Sztul R, Kujawski M, Szyfter W, Szyfter K. CYP1A1,CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma. Mutat Res 2005;574:112-23. |
|15.||Abdel-Rahman SZ, Anwar WA, Abdel-Aal WE, Ghoneim MA, Au WW. The CYP2D6 extensive metabolizer genotype is associated with increased risk for bladder cancer. Cancer Lett 1997;119:115-22. |
|16.||Roy B, Sikdar N. Polymorphisms in Drug-metabolizing Genes and Risk of Head and Neck Squamous Cell Carcinoma. Int J Hum Genet 2003;3:99-108. |
|17.||Fandino MQ, Hitt R, Medina PP, Gamarra S, Manso L, Funes HC, et al. DNA-Repair Gene Polymorphisms Predict Favourable Clinical Outcome Among Patients With Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Cisplatin-Based Induction Chemotherapy. J Clin Oncol 2006;24:4333-9. |
|18.||Gurubhagavatula S, Liu G, Park S, Zhou W, Su L, Wain JC, et al. XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol 2004:22:2594-601. |
|19.||Smith CAD, Moss JE, Gough AC, Spurr NK, Wolf CR. Molecular genetic analysis of the cytochrome P450-debrisoquine hydroxylase locus and association with cancer susceptibility. Environ Health Perspect 1992;98:107-12. |
|20.||Smith TJ, Guo Z, Gonzalez FJ, Guengerich FP, Stoner GD, Yang CS. Metabolism of 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone in human lung and liver microsomes and cytochromes P-450 expressed in hepatoma cells. Cancer Res 1992;52:1757-63. |
|21.||Sobti RC, Onsory K, Al-Badran AI, Kaur P, Watanabe M, Krishan A, et al. CYP17, SRD5A2, CYP1B1, and CYP2D6 gene polymorphisms with prostate cancer risk in North Indian population. DNA Cell Biol 2006;25:287-94. |
|22.||International Agency for Research on Cancer. Alcohol drinking. IARC monographs on the evaluation of carcinogenic risks to humans. vol 44. Lyon: IARC; 1988. |
|23.||Goshman L, Fish J, Roller K. Pharmacotherapy Perspectives Clinically Significant Cytochrome P450 Drug Interactions. In: Vermeulen L, column editor. Center for Drug Policy. USA: University of Wisconsin Hospital and Clinics. |
|24.||Waxman DJ. Steroid hormones and other physiologic regulators of liver cytochromes P450: Metabolic reactions and regulatory pathways. In: Jefcoate CR, guest editor. Vol. 14. Advances in Molecular and Cell Biology; 1996. p. 341-74. |
|25.||Yadav SS, Ruwali M, Shah PP, Mathur N, Singh RL, Pant MC, et al. Association of poor metabolizers of cytochrome P450 2C19 with head and neck cancer and poor treatment response. Mutat Res 2008;644:31-7. |
|26.||Marion LW, Pankaj B, Ilham C, John LM, David AF, Irving WW. A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer. Br J Clin Pharmacol 2000;49:485-8. |
|27.||Ando Y, Fuse E, Figg WD. Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res 2002;8:1964-73. |
|28.||Nagasubramanian R, Innocenti F, Ratain MJ. Pharmacogenetics in cancer treatment. Annu Rev Med 2003;54:437-52. |
|29.||Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC, et al. Excision repair cross complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 2004;10:4939-43. |
|30.||Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M, et al. Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 2004;15:1194-203. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]