P53 Arg72Pro, CASP3 A-928G, CASP9 A-1263G and C-712T polymorphisms, related to apoptosis, in cisplatin pharmacogenetic associated with radiotherapy in patients with squamous cell carcinoma of head and neck

Abstract

The squamous cell carcinoma of head and neck (SCCHN) is a serious global health problem. Cisplatin (CDDP) combined with radiotherapy is given as neoadjuvant, adjuvant, or definitive palliation for patients with the disease. It is well known that both the response to treatment as their side effects vary from individual to individual, which appears to be explained, at least in part, by the genetic variability in the metabolism of CDDP. The aim of this study is to assess if the abilities inherited apoptosis of damaged cells, mediated by P53, CASP3 and CASP9 enzymes, alter the therapeutic and side effects of treatment of patients with SCCHN. It will be evaluated, prospectively, 100 patients with SCCHN at the Outpatient Oncology Clinic of the Clinical Hospital of the University of Campinas, who will receive CDDP (80-100 mg/m2/dose, D1, D22 and D43) and radiotherapy (7000 cGy , 35 sessions) as neoadjuvant treatment, definitive or palliative treatment of disease. Patients will receive standard supportive therapy with hydration, antiemetics, analgesics, laxatives and antidiarrheals. Side effects to treatment will be evaluated and graded (grades 1-4) by means of questionnaire and physical examination, according to the criteria of the National Cancer Institute (NCI). Renal toxicities and audio will be evaluated by serum creatinine, glomerular filtration rate with ethylenediaminetetraacetic acid labeled with 51-chromium (51 Cr-EDTA) and acoustic acuity tests, respectively, before and after treatment. The genotypes of P53 Arg72Pro, CASP3 A-928G, e CASP9 A-1263G e C-712T polymorphisms will be analyzed by polymerase chain reaction (PCR) and enzyme digestion of DNA samples from peripheral blood. The measurements of urinary CDDP will be performed by high performance liquid chromatography (HPLC) after each dose of chemotherapy. The response rate to treatment will be evaluated by physical examination, the direct Laryngoscopy (when appropriate), computed tomography of the neck and chest (when appropriate), according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The differences between groups will be calculated by Fisher's exact test or chi-square test. We believe that our results may help to stratify groups of individuals who deserve to receive different doses of CDDP in the treatment of SCCHN.