Pharmacogenetics of cisplatin in head and neck squamous cell carcinoma

Abstract

The head and neck squamous cell carcinoma (HNSCC) is a serious health problem worldwide. Cisplatin (CDDP) associated with radiotherapy is used in the treatment for HNSCC patients. It is well known that both the response to treatment and its collateral effects vary from individual to individual. A possible explanation for this can be the genetic variability in the metabolism of CDDP. The aim of this study is to verify if the inherited ability to CDDP detoxification, in the DNA damage repair induced for it and apoptosis of damage cells alter therapeutic and collateral effects of treatment in patients with HNSCC. It will be evaluated, prospectively, 100 patients with HNSCC at the Clinical Hospital, State University of Campinas, will receive CDDP (80-100 mg/m2/dose, D1, D22 and D43) and radiotherapy (7,000 cGy, 35 sessions), as neoadjuvant, definitive or palliative treatment of the disease. The human papillomavirus identification will be performed by immunohistochemistry of tumor fragments obtained at the diagnosis. Patients will receive standardized supportive. Treatment collateral effects will be scored (grade 1 to 4) by a specific questionnaire and physical examination, according to the criteria of the National Cancer Institute (NCI). The renal and auditory toxicities will be evaluated through serum creatinine, glomerular filtration rate with EDTA-51Cr and acoustic acuity tests, respectively, before and after treatment. The polymorphisms genotypes GSTM1, GSTT1, GSTP1 Ile105Val, XPC Lys939Gln, XPD Lys751Gln, XPD Asp312Asn, XPF T30028C, ERCC1 C118T, MSH2 IVS1+9G>C, MSH3 Ala1045Thr, MLH1 G-93A, EXO1 P757L, EXO1 K589E, P53 Arg72Pro, CASP3 A-928G, CASP3 IVS1-15G>T, CASP8 -652 6N ins/del, CASP9 A-1263G, CASP9 C-712T, FAS G-1377A, FAS A-670G, FASL C-844T will be analyzed by polymerase chain reaction (PCR) and enzymatic digestion or Real-Time PCR of DNA samples extracted from peripheral blood. The doses of CDDP in urine will be performed by high performance liquid chromatography (HPLC). The response treatment will be assessed by physical examination, direct nasofibrolaryngoscopy and computed tomography of the neck and chest, according to Response Evaluation Criteria in Solid Tumors (RECIST) and single photon emission computer tomography (SPECT-CT). The differences between groups will be calculated by Fisher's exact test or chi-square. We believe that the results may contribute to stratify groups of individuals who deserve to receive different doses of CDDP in the treatment of HNSCC. (AU)