RESUMO
Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-ß estradiol analogs as cancer treatment.
Assuntos
Antimitóticos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antimitóticos/classificação , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/metabolismo , Taxoides/uso terapêutico , Alcaloides de Vinca/uso terapêuticoRESUMO
Antimitotic agents have been the most successful pharmacological agents for the treatment of cancer. The term "antimitotic agent" has traditionally been synonymous with tubulin-targeting compounds, but as a consequence of the large number of new compounds and mechanisms that have been identified recently, a much broader definition is currently needed. This review attempts to provide a broad overview of compounds and their cognate protein targets which result in a block in mitosis. Focus has been placed on agents that act directly on the mitotic machinery rather than on targets further upstream such as growth factor receptors.
Assuntos
Antimitóticos/farmacologia , Produtos Biológicos/farmacologia , Actinas/metabolismo , Animais , Antimitóticos/classificação , Sítios de Ligação/efeitos dos fármacos , Produtos Biológicos/classificação , Colchicina/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Humanos , Cinesinas/antagonistas & inibidores , Proteínas dos Microtúbulos/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/genética , Inibidores de Proteassoma , Compostos de Sulfidrila/farmacologia , Inibidores da Topoisomerase , Tubulina (Proteína)/efeitos dos fármacos , Alcaloides de Vinca/farmacologiaRESUMO
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
