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Fármacos de Platina no tratamento oncológico: mecanismos de resistência
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Advisor(s)
Abstract(s)
Na década de 1960, a descoberta da atividade anticancerígena da cisplatina e a sua eficácia clínica despertaram um grande interesse na investigação de compostos de coordenação para tratamento do cancro. Para além da cisplatina, surgiram outros complexos de platina, como a carboplatina e a oxaliplatina. Estes compostos são amplamente utilizados no tratamento de vários tipos de cancro, incluindo testicular, pulmonar, ovário e bexiga.
O mecanismo de ação dos fármacos de platina é bastante complexo, sendo que a formação de adutos inter ou intracadeias com o ADN nuclear é uma das vias mais estudadas e reconhecidas. A formação destes adutos resulta na interrupção dos processos de replicação e trancrição do ADN, promovendo desta forma apoptose. No entanto, o ADN nuclear não é o único alvo, existem outros alvos celulares que contribuem para o efeito dos fármacos de platina. O complexo de cisplatina ataca as mitocôndrias e desencadeia a produção de espécies reativas de oxigénio, destruindo os lisossomas e por sua vez, induzindo a libertação de proteáses lisossomais que degradam o retículo endoplasmático. Estes complexos podem ainda, através da formação de adutos com grupos funcionais em proteínas, em particular com átomos de enxofre presentes nos resíduos de cisteína e metionina, alterar a função proteica contribuindo para a morte celular.
Apesar da eficácia comprovada, a resistência aos fármacos de platina representa um grande desafio no meio oncológico. As células cancerígenas podem desenvolver resistência através de diversos mecanismos, como a alteração da captação/efluxo de fármaco, a inativação da cisplatina por moléculas contendo tiol, e a capacidade de regeneração do ADN danificado.
Compreender estes mecanismos de resistência é crucial para o desenvolvimento de novas estratégias terapêuticas. Ao longo desta monografia são demonstrados diversos mecanismos de resistência, bem como formas de ultrapassar e otimizar o tratamento farmacoterapêutico.
In the 1960s, the discovery of the anticancer activity of cisplatin and its clinical efficacy sparked significant interest in investigating coordination compounds for cancer treatment. In addition to cisplatin, other platinum complexes emerged, such as carboplatin and oxaliplatin. These compounds are widely used in the treatment of various types of cancer, including testicular, lung, ovarian, and bladder. The mechanism of action of platinum drugs is quite complex, with the formation of inter- or intra-strand DNA adducts being one of the most studied and recognized pathways. The formation of these adducts results in the disruption of DNA replication and transcription processes, thereby promoting apoptosis. However, nuclear DNA is not the only target, there are other cellular targets that contribute to the effect of platinum drugs. Cisplatin, for instance, attacks mitochondria and triggers the production of reactive oxygen species, leading to the destruction of lysosomes and the subsequent release of lysosomal proteases that degrade the endoplasmic reticulum. These complexes can also form adducts with the functional groups in proteins, particularly with sulfur atoms in cysteine and methionine residues, altering protein function and contributing to the cell death. Despite their proven efficacy, resistance to platinum drugs presents a major challenge in oncology. Cancer cells can develop resistance through various mechanisms, such as altering drug uptake/efflux, inactivating cisplatin via thiol-containing molecules, and repairing damaged DNA. Understanding these resistance mechanisms is crucial for developing new therapeutic strategies. Throughout this monograph, various mechanisms of resistance are demonstrated, as well as ways of overcoming and optimising pharmacotherapeutic treatment.
In the 1960s, the discovery of the anticancer activity of cisplatin and its clinical efficacy sparked significant interest in investigating coordination compounds for cancer treatment. In addition to cisplatin, other platinum complexes emerged, such as carboplatin and oxaliplatin. These compounds are widely used in the treatment of various types of cancer, including testicular, lung, ovarian, and bladder. The mechanism of action of platinum drugs is quite complex, with the formation of inter- or intra-strand DNA adducts being one of the most studied and recognized pathways. The formation of these adducts results in the disruption of DNA replication and transcription processes, thereby promoting apoptosis. However, nuclear DNA is not the only target, there are other cellular targets that contribute to the effect of platinum drugs. Cisplatin, for instance, attacks mitochondria and triggers the production of reactive oxygen species, leading to the destruction of lysosomes and the subsequent release of lysosomal proteases that degrade the endoplasmic reticulum. These complexes can also form adducts with the functional groups in proteins, particularly with sulfur atoms in cysteine and methionine residues, altering protein function and contributing to the cell death. Despite their proven efficacy, resistance to platinum drugs presents a major challenge in oncology. Cancer cells can develop resistance through various mechanisms, such as altering drug uptake/efflux, inactivating cisplatin via thiol-containing molecules, and repairing damaged DNA. Understanding these resistance mechanisms is crucial for developing new therapeutic strategies. Throughout this monograph, various mechanisms of resistance are demonstrated, as well as ways of overcoming and optimising pharmacotherapeutic treatment.
Description
Keywords
Platina Resistência Cancro Tratamento Cisplatina Atividade anticancerígena