ABSTRACT
The main goal of chemotherapeutic drugs is to induce massive cell death in tumors. Cisplatin is an antitumor drug widely used to treat several types of cancer. Despite its remarkable efficiency, most tumors show intrinsic or acquired drug resistance. The primary biological target of cisplatin is genomic DNA, and it causes a plethora of DNA lesions that block transcription and replication. These cisplatin-induced DNA lesions strongly induce cell death if they are not properly repaired or processed. To counteract cisplatin-induced DNA damage, cells use an intricate network of mechanisms, including DNA damage repair and translesion synthesis. In this review, we describe how cisplatin-induced DNA lesions are repaired or tolerated by cells and focus on the pivotal role of DNA repair and tolerance mechanisms in tumor resistance to cisplatin. In fact, several recent clinical findings have correlated the tumor cell status of DNA repair/translesion synthesis with patient response to cisplatin treatment. Furthermore, these mechanisms provide interesting targets for pharmacological modulation that can increase the efficiency of cisplatin chemotherapy.
Subject(s)
Humans , DNA Damage/genetics , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/genetics , DNA Repair/genetics , Antineoplastic Agents/therapeutic use , DNA Damage/drug effectsABSTRACT
A descoberta de que nossas células dispõem de um mecanismo de silenciamento gênico empregando RNA interferência ainda é muito recente. Apesar disso, em menos de uma década a investigação científica já alcançou progresso, suficiente para muito brevemente nos apropriarmos desse conhecimento com fins terapêuticos. Duplexes de RNA são potenciais fármacos e há investimentos altos nessa nova abordagem. Aparentemente, a promessa de terapia gênica parece finalmente atingir sua maturidade com essas novas ferramentas.
The discovery of gene silencing mechanisms in our own cells using RNA interference is very recent. However, in less than a decade, the scientific investigation have progressed enough to make us see that, very soon, we will use this knowledge for therapeutic purposes. RNA duplexes are potential pharmaceutical drugs and there are high investments in this new strategy. The promising gene therapy seems to finally reach maturity with these new tools.
Subject(s)
Gene Silencing , Neoplasms/therapy , RNA Interference , Biological Therapy , Genetic Therapy/trends , VirusesABSTRACT
Avanços na tecnologia de DNA recombinante forneceram novas perspectivas em todas as áreas da bilogia. No estudo de mutagênese e reparo de DNA, a clonagem de vários genes envolvidos na manutençäo do material genético, assim como o desenvolvimento de diferentes métodos para o estudo de genotoxicidade, permitiram ampliar as possibilidades de investigar os mecanismos celulares envolvidos em alteraçöes genéticas induzidas ou espontâneas. Neste trabalho, descrevemos a utilizaçäo de novas ferramentas genéticas, os vetores-ponte, na busca de informaçöes dos processos pelos quais lesöes no DNA, induzidas por agentes químicos ou físicos, provocam mutaçöes no genoma de células de mamíferos