title: Genetic variability & chemotoxicity of 5-fluorouracil & cisplatin in head & neck cancer patients: a preliminary study.
abstract: background & objectives: The efficacy and toxicity of a given chemotherapy regimen varies widely among patients due to the inherited variability of genes that are involved in drug metabolism. There are several crucial enzymes identified involving metabolism of 5-fluorouracil (5-FU) and cisplatin, which are polymorphic. We studied head and neck cancer patients (n=23) on 5-FU and cisplatin combination therapy attending a tertiary care cancer research institute in Gujarat, India, to understand the effect of a particular genotype on toxicity.
  
  
  METHODS
  The patients were genotyped for dihydropyrimidine (DPYD) (85T>C, IVS14+1G>A, 2846A>T, 2194G>A), thymidylate synthase (TYMS) [28bp tandem repeat in the promoter enhancer region (TSER)], methylenetetrahydrofolate reductase (MTHFR) (677C>T, 1298A>C), glutathione S-transferase P1(GSTP1) (Ile105Val), glutathione S-transferase T1 (GSTT1) (null allele) and glutathione S-transferase M1 (GSTM1) (null allele) by multiplex allele-specific PCR and long range PCR.
  
  
  RESULTS
  Of the 23 (19 males 4 females, age range 18-16 yr) patients, two had grade 3 and 4 toxicity while the remaining 21 had 0 to 2 grade toxicity after treatment with 5-FU and cisplatin combination therapy. An association between the genotype of GSTM1 (+/- and -/-) and the toxicity of cisplatin (P=0.043) was observed.
  
  
  CONCLUSIONS
  The findings of this preliminary study suggested an association between the variants of GSTM1 and toxicity observed due to cisplatin. Well planned studies on a large sample of head and neck cancer patients need to be conducted to understand the effects of these genetic variants on toxicity and efficacy of anticancer drugs.
authors.affiliation: B.V. Patel Pharmaceutical Education & Research Development (PERD) Centre, Ahmedabad, India.
authors.forename: Dipali
authors.initials: D
authors.lastname: Dhawan
authors.forename: Harsha
authors.initials: H
authors.lastname: Panchal
authors.forename: Shilin
authors.initials: S
authors.lastname: Shukla
authors.forename: Harish
authors.initials: H
authors.lastname: Padh
mesh_terms: D000293:Adolescent; D000328:Adult; D054316:Biomarkers, Pharmacological; D002945:Cisplatin / Q000008:administration & dosage*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D056726:Genetic Association Studies; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D054316:Biomarkers, Pharmacological; D002945:Cisplatin; D005472:Fluorouracil; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C573423:MTHFR protein, human; C413545:glutathione S-transferase T1