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Master's Dissertation
DOI
10.11606/D.9.2013.tde-27022014-103617
Document
Author
Full name
Graziele Fonseca de Sousa
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2013
Supervisor
Committee
Souza, Gisele Monteiro de (President)
Barros, Mário Henrique de
Engler, Silvya Stuchi Maria
Title in Portuguese
Identificação de alvos moleculares associados à resistência e a sensibilidade aos antitumorais carboplatina e análogos de rebecamicina utilizando Saccharomyces cerevisiae como modelo celular
Keywords in Portuguese
Análogos de rebecamicina
Câncer
Carboplatina
Leveduras
Abstract in Portuguese
Existe um grande interesse das indústrias farmacêuticas em encontrar um tratamento adequado para os pacientes com câncer que apresentaram resistência aos medicamentos comumente utilizados para o combate dessa neoplasia. Sendo assim, se faz necessário a busca de novos marcadores genéticos que estejam associados à predisposição do paciente a reagir ao efeito da droga de maneira diferente do esperado. Para isso, vários estudos vêm sendo desenvolvidos, baseados nos medicamentos anticancerígenos. Entre esses medicamentos podemos destacar os agentes quimioterápicos a base de platina, como a carboplatina, cisplatina, oxaliplatina e a nedaplatina, que agem eliminando as células cancerosas através da formação de adutos nas bases de purina do DNA nuclear e a rebecamicina, um antitumoral que possui a capacidade de inibir a ação catalítica das topoisomerases I, ainda em teste clínico. Desse modo, este estudo teve a perspectiva de encontrar mutantes de leveduras resistentes a carboplatina e análogos de rebecamicina. Como resultado, identificamos 19 genes associados à resistência a carboplatina, sendo que 6 deles possuem genes ortólogos em humanos associados principalmente ao mecanismo de reparo de DNA e ao transporte celular. Foram também identificadas 9 linhagens que estavam associadas a sensibilidade a carboplatina sendo que 3 delas possuem deleções em genes com ortólogos humanos, que estão associados ao transporte endossomal, ao ribossomo e ao bloqueio do ciclo celular na fase G1. Na busca por um novo composto antitumoral derivado de rebecamicina, identificamos Reb C como um análogo promissor, já que apresentou 9 genes associados a resistência, dos quais 2 deles possuem ortólogos humanos relacionados ao ribossomo e ao proteassoma
Title in English
Identification of molecular targets associated to resistance and sensitivity to anticancer carboplatin and analogs of rebeccamycin using Saccharomyces cerevisiae as a model cell
Keywords in English
Cancer
Carboplatin
Rebeccamycin analogs
Yeast
Abstract in English
There is a strong interest from pharmaceutical companies in finding an appropriate treatment for patients with cancer who had resistance to drugs commonly used to fight this disease. Therefore, it is necessary to search for new genetic markers that are associated with the patient's predisposition to react to the drug differently than expected. Aiming this, several studies have been developed based on anticancer drugs. Among these drugs can be highlighted the chemotherapeutic agents based on platinum, such as carboplatin, cisplatin, oxaliplatin and nedaplatin, which act by eliminating cancer cells through the formation of adducts with the purine bases of nuclear DNA and the rebeccamycin, an antitumor that has the ability to inhibit the catalytic action of topoisomerase I, still in clinical trial. This study aimed to find yeast resistant mutants to carboplatin and rebeccamycin analogs. As a result, we identified 19 genes associated with resistance to carboplatin, 6 of them presenting orthologous genes in humans, which are mainly associated to the mechanism of DNA repair and to cellular transport. 9 strains were also identified which are associated with carboplatin sensitivity, 3 possessing their orthologous in humans associated with endosomal transport, ribosome and cell cycle arrest in the G1 phase. In a search for a new antitumor compound derived from rebeccamycin, we identified the Reb C analog as promising, since it featured nine genes associated with resistance to it, among 2 of them have human counterparts related to the ribosome and the proteasome.
 
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Publishing Date
2014-03-24
 
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