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Taxanos: novas moléculas, novos sistemas de vectorização e estratégias terapêuticas para ultrapassar mecanismos de resistência
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Abstract(s)
Os taxanos foram introduzidos na terapêutica antineoplásica há mais de três décadas, mas continuam a ser dos fármacos mais usados no tratamento de diversos tumores malignos. Apresentam um mecanismo de ação único, sendo agentes estabilizadores dos microtúbulos. No entanto, os taxanos clássicos apresentam algumas limitações relacionadas com a sua baixa hidrossolubilidade, toxicidade e aparecimento de resistências. O melhor conhecimento da relação estrutura-atividade destes fármacos e dos mecanismos moleculares envolvidos no aparecimento de fenómenos de resistência permitiu que, ao longo dos últimos anos, tenham sido apresentadas estratégias para ultrapassar as referidas limitações. Assim, foram desenvolvidas novas formas de vectorização destas moléculas e sintetizados novos taxanos.
A investigação nesta área permitiu já a introdução no mercado de algumas novas formulações de taxanos (as quais apresentam menor toxicidade do que as iniciais) – caso do Abraxane® e do Genexol-PM®, e a avaliação de muitas outras (incluindo alguns novos taxanos), as quais se encontram atualmente em fase de ensaios pré-clínicos e clínicos. Estes novos taxanos e/ou novas formas de vectorização que aguardam aprovação pelas entidades reguladoras têm revelado várias vantagens, nomeadamente a possibilidade de administração por via oral, a mais reduzida toxicidade e a capacidade de atuar em tumores que se revelam resistentes aos taxanos clássicos.
Este trabalho de revisão narrativa da literatura científica incidirá na abordagem das formulações mais recentes de taxanos, realçando as estratégias mais promissoras para ultrapassar as limitações associadas à terapêutica atual com estes fármacos e apontando possíveis áreas de evolução futura.
Taxanes were introduced in anticancer therapy more than three decades ago, but they continue to be one of the most used drugs in the treatment of various malignant tumors. They have a unique mechanism of action, being microtubule stabilizing agents. However, classical taxanes have some limitations related to their low water solubility, toxicity and emergence of resistance. The better knowledge of the structure-activity relationship of these drugs and the molecular mechanisms involved in the emergence of resistance phenomena has allowed, over the last few years, to present strategies to overcome these limitations. Thus, new ways of targeting these molecules were developed and new taxanes were synthesized. Research in this area has already allowed the introduction on the market of some new formulations of taxanes (which have less toxicity than the initial ones) – such as Abraxane® and Genexol-PM®, and the evaluation of many others (including some new taxanes), which are currently undergoing pre-clinical and clinical trials. These new taxanes and/or new forms of vectoring that are awaiting approval by the regulatory authorities have revealed several advantages, namely the possibility of oral administration, the lowest toxicity and the ability to act on tumors that prove to be resistant to classical taxanes. This narrative review of the scientific literature will focus on the approach of the most recent formulations of taxanes, highlighting the most promising strategies to overcome the limitations associated with current therapy with these drugs and pointing out possible areas for future evolution.
Taxanes were introduced in anticancer therapy more than three decades ago, but they continue to be one of the most used drugs in the treatment of various malignant tumors. They have a unique mechanism of action, being microtubule stabilizing agents. However, classical taxanes have some limitations related to their low water solubility, toxicity and emergence of resistance. The better knowledge of the structure-activity relationship of these drugs and the molecular mechanisms involved in the emergence of resistance phenomena has allowed, over the last few years, to present strategies to overcome these limitations. Thus, new ways of targeting these molecules were developed and new taxanes were synthesized. Research in this area has already allowed the introduction on the market of some new formulations of taxanes (which have less toxicity than the initial ones) – such as Abraxane® and Genexol-PM®, and the evaluation of many others (including some new taxanes), which are currently undergoing pre-clinical and clinical trials. These new taxanes and/or new forms of vectoring that are awaiting approval by the regulatory authorities have revealed several advantages, namely the possibility of oral administration, the lowest toxicity and the ability to act on tumors that prove to be resistant to classical taxanes. This narrative review of the scientific literature will focus on the approach of the most recent formulations of taxanes, highlighting the most promising strategies to overcome the limitations associated with current therapy with these drugs and pointing out possible areas for future evolution.
Description
Keywords
Taxanos Taxanos e nano Taxanos e multirresistência Novos taxanos Taxanos e direcionamento Taxanos orais Taxanos e análogos Taxanes Taxanes and nano Taxanes and multi-resistance New taxanes Taxanes and targeting Oral taxanes Taxanes and analogues