title: Association of genetic variability in enzymes metabolizing chemotherapeutic agents with treatment response in head and neck cancer cases.
abstract: OBJECTIVE
  The prevalence of genetic variants of thiopurine S-methyltransferse (TPMT) and dihydropyrimidine dehydrogenase (DPD) in healthy controls (500) and the treatment response in 500 cases of head and neck cancer of north Indian origin was studied.
  
  
  METHODS
  Blood collected from all the subjects was used for isolation of DNA followed by genotyping studies. The cases received cisplatin and 5-fluorouracil (5-FU) or chemo-radiotherapy and treatment response was measured using WHO criteria.
  
  
  RESULTS
  Low frequency of heterozygous mutant genotypes of TPMT*2 (2%), TPMT*3B (2.2%), TPMT*3C (4.6%), DPD IVS14+1G>A (3.6%) and G1601A (3%) was observed, although no homozygous mutants could be identified. Treatment response studies in cases receiving cisplatin and 5-FU or chemo-radiotherapy revealed that the number of nonresponders was higher in cases who carried variant genotypes of TPMT*3B (62.50%) or TPMT*3C (59.26%) or DPD IVS14+1G>A (61.90%). Likewise, the number of nonresponders was still higher in cases carrying combination of these genetic variants. Furthermore, the frequency of nonresponders was higher in cases who carried the variant genotypes of TPMT or DPD and were also tobacco users.
  
  
  CONCLUSIONS
  Our data clearly show that TPMT and DPD genes are polymorphic in the north Indian population and may be important in determining the treatment response in cases. The data have also suggest tobacco may play an important role in determining the outcome of cancer therapy and there is an urgent need for assessment of drugs for their efficacy/toxicity in smokers compared to nonsmokers.
authors.affiliation: Department of Radiotherapy, King George's Medical University, Lucknow, India.|Amity University, Lucknow Campus, Gomti Nagar, Lucknow, India.
authors.forename: Ankur
authors.initials: A
authors.lastname: Dhawan
authors.affiliation: Amity Institute of Biotechnology, Amity University Haryana, Manesar, Gurgaon, India.
authors.forename: Munindra
authors.initials: M
authors.lastname: Ruwali
authors.affiliation: Department of Radiotherapy, King George's Medical University, Lucknow, India.
authors.forename: Mohan C
authors.initials: MC
authors.lastname: Pant
authors.affiliation: Amity University, Lucknow Campus, Gomti Nagar, Lucknow, India.
authors.forename: Qamar
authors.initials: Q
authors.lastname: Rahman
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Devendra
authors.initials: D
authors.lastname: Parmar
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000532:radiotherapy; D016022:Case-Control Studies; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D005787:Gene Frequency; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D007194:India; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D004273:DNA, Neoplasm; D042943:Dihydrouracil Dehydrogenase (NADP); D008780:Methyltransferases; C022745:thiopurine methyltransferase; D002945:Cisplatin; D005472:Fluorouracil
keywords: 5-fluorouracil; cisplatin; head and neck cancer; polymorphism; treatment response