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MLH1 G-93A, MSH2 IVS1+9G>C, MSH3 Ala1045Thr, EXO1 P757L and EXO1 K589E Polymorphisms Related to DNA Repair by Mismatch Repair in Cisplatin Pharmacogenetic Associated with Radiotherapy in Patients with Squamous Cell Carcinoma of Head and Neck

Grant number: 12/01418-6
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2012
Effective date (End): February 28, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Carmen Silvia Passos Lima
Grantee:Guilherme Augusto da Silva Nogueira
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


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 verify if the inherited abilities in the repair of DNA lesions, mediated by MLH1, MSH2, MSH3 and EXO1 enzymes, alter the therapeutic and side effects of the treatment of SCCHN patients. 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, definitive or palliative treatment of the disease. Patients will receive standard supportive therapy with hydration, antiemetics, analgesics, laxatives and antidiarrheals. Side effects to treatment will be evaluated and graded (degrees 1-4) by specific questionnaire and physical examination, according to the criteria of the National Cancer Institute (NCI). Renal and auditory toxicities 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 MLH1 G-93A, MSH2 IVS1+9G>C, EXO1 P757L and EXO1 K589E polymorphisms will be analyzed by polymerase chain reaction (PCR) and enzymatic digestion of DNA samples extracted from peripheral blood. Since the genotypes of the MSH3 Ala1045Thr polymorphism will be evaluated by real-time PCR. 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, direct nasofibrolaryngoscopy (when appropriate), computed tomography of the neck and chest (when appropriate), according to Response Evaluation Criteria in Solid Tumors (RECIST). 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.

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
NOGUEIRA, Guilherme Augusto da Silva. Polymorphisms in mismatch DNA repair genes in cisplatin pharmacogenetics associated with radiotherapy in patients with head and neck squamous cell carcinoma. 2014. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.

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