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| Author(s): |
Guilherme Augusto da Silva Nogueira
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2014-08-26 |
| Examining board members: |
Carmen Silvia Passos Lima;
Carmen Sílvia Bertuzzo;
Gilberto Castro Junior
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| Advisor: | Carmen Silvia Passos Lima |
| Abstract | |
Cisplatin (CDDP) associated with radiotherapy (RT) is used in treatment of patients with head and neck squamous cell carcinoma (HNSCC). It is well known that both response to treatment and side effects vary among individuals. A possible explanation for this may be the genetic variability in metabolism of CDDP. The aim of this study was to acess if inherited ability to repair DNA damage, mediated by MLH1, MSH2, MSH3 and EXO1 enzymes change the therapeutic side effects and urinary concentration of CDDP in HNSCC patients. We evaluated prospectively, 90 consecutive HNSCC patients of UNICAMP¿s Hospital, who received CDDP-associated RT as neoadjuvant, definitive or palliative treatment. Genotypes of MLH1 G-93A, MSH2 IVS1+9G>C, MSH3 Ala1045Thr, EXO1 P757L and EXO1 K589E polymorphisms were analyzed by polymerase chain reaction (PCR) and restriction enzyme digestion or real-time PCR in DNA of peripheral blood. Treatment response was assessed by computed tomography of the neck, according to Response Evaluation Criteria in Solid Tumors 1.1. Treatment side effects were ranked through questionnaire and laboratory tests, according to the National Cancer Institute 4.0. Renal and hearing toxicities were assessed using, respectively, estimated creatinine clearance and glomerular filtration 51Cr-EDTA, and audiometry, measured before and after treatment. Urinary doses of CDDP were performed by high performance liquid chromatography. Statistical significance of differences between groups was calculated by Fisher's exact probability test or chi-square, and multiple logistic regression. MLH1 GG+GA genotype was associated with lower incidence of nausea. MSH2 CC genotype was associated with improvement of hearing acuity and tendency of lower CDDP urinary excretion. MSH3 AlaAla+AlaThr and AlaAla genotypes were associated with high ototoxicity and high nephrotoxicity, and worsening of hearing acuity, respectively. EXO1 ProLeu genotype was associated with high ototoxicity and worsening of hearing acuity. EXO1 GluLys+LysLys and LysLys genotypes were associated with lower complete response, and worsening of hearing acuity and and tendency to high nephrotoxicity, respectively. We conclude that the referred polymorphisms, related to inherited abnormalities in DNA repair, may change rate of complete response, side effects, and CDDP urinary concentration in patients with HNSCC treated with CDDP and RT. We believe that these results may contribute to the future personalized treatment of HNSCC patients (AU) | |
| FAPESP's process: | 12/01418-6 - 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 |
| Grantee: | Guilherme Augusto da Silva Nogueira |
| Support Opportunities: | Scholarships in Brazil - Master |