RESUMO
Epothilones represent a novel class of anticancer drugs which inhibit the cell cycle and strongly influence cell division. The biological activity of epothilones is associated with their capacity to bind to the protein tubulin of microtubules and to disturb the dynamic equilibrium between microtubule assembling and disassembling. Consequently, in dividing cells, it leads to mitotic arrest and to apoptotic cell death. A number of epothilones demonstrate a potent inhibitory effect on cell proliferation in human tumor cell lines, as well as antitumor activity in experimental animals bearing human tumor xenografts. This review will focus on the recent preclinical studies of the in vitro and in vivo activities of four epothilones, EPO-906, BMS-247550, KOS-862 and BMS-310705. Several epothilones are undergoing clinical evaluation and are promising candidates for advanced cancer therapy.
Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Epotilonas , Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Epotilonas/química , Epotilonas/farmacologia , Epotilonas/uso terapêutico , Humanos , Estrutura Molecular , Neoplasias/genética , Neoplasias/patologiaRESUMO
Kosan and Roche are developing the microtubule inhibitor epothilone D (KOS-862 and NSC-703147), an analog of epothilone B for the potential treatment of cancer. Phase II trials in colorectal, metastatic breast and non-small-cell lung cancers were initiated in December 2003.
Assuntos
Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Epotilonas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/química , Drogas em Investigação/farmacologia , Epotilonas/efeitos adversos , Epotilonas/química , Epotilonas/farmacologia , HumanosRESUMO
Bristol-Myers Squibb, in collaboration with the German Research Centre for Biotechnology, is developing BMS-310705, an epothilone analog, for the potential treatment of cancer. By April 2002, phase I trials of BMS-310705 were underway.
Assuntos
Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Epotilonas/uso terapêutico , Animais , Antineoplásicos/química , Ensaios Clínicos Fase I como Assunto/métodos , Drogas em Investigação/química , Epotilonas/química , HumanosRESUMO
Allos Therapeutics Inc is developing the hemoglobin allosteric modifier efaproxiral as a potential radiosensitizer and chemotherapy enhancer in cancer therapy.
Assuntos
Compostos de Anilina/farmacologia , Neoplasias/radioterapia , Propionatos/farmacologia , Radiossensibilizantes/farmacologia , Compostos de Anilina/efeitos adversos , Compostos de Anilina/síntese química , Compostos de Anilina/uso terapêutico , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Contraindicações , Humanos , Propionatos/efeitos adversos , Propionatos/síntese química , Propionatos/uso terapêutico , Radiossensibilizantes/efeitos adversos , Radiossensibilizantes/síntese química , Radiossensibilizantes/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Ethylene oxide (EtO), propylene oxide (PO) and epichlorohydrin (ECH) are important industrial chemicals widely used as intermediates for various synthetic products. EtO and PO are also environmental pollutants. In this review we summarize data published during the period 1990-2001 concerning both the genotoxic and carcinogenic effects of these epoxides in humans. The use of DNA and hemoglobin adducts as biomarkers of exposure and the role of polymorphism, as well as confounding factors, are discussed. We have also included recent in vitro data comprising genotoxic effects induced by EtO, PO and ECH in mammalian cells. The uncertainties regarding cancer risk estimation still persist, in spite of the large database collected.
Assuntos
Epicloroidrina/toxicidade , Compostos de Epóxi/toxicidade , Óxido de Etileno/toxicidade , Mutagênicos/toxicidade , Mutação , Neoplasias/induzido quimicamente , Carcinógenos/toxicidade , Estudos de Coortes , DNA/efeitos dos fármacos , DNA/metabolismo , Desinfetantes/toxicidade , Poluentes Ambientais/toxicidade , Hemoglobinas/química , Hemoglobinas/metabolismo , Humanos , Testes de Mutagenicidade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Exposição Ocupacional , Polimorfismo Genético , Medição de Risco , FumarRESUMO
Cytotoxic and mutagenic effects of aphidicolin (APC), an inhibitor of DNA polymerases alpha and delta, were studied in human diploid VH-10 fibroblasts. The cells were treated (2 or 4h) with APC at concentration ranges of 10-40 microM. The effect of APC on cell survival after 4 h treatment was significantly higher than after 2 h treatment. The mutagenicity of APC was investigated at the HPRT locus, and the frequency of HPRT mutants was estimated by selection in medium containing 6-thioguanine (6-TG). Treatment of fibroblast cells with 20 microM of APC for 2 or 4 h resulted approximately in 5 or 10 times increase of 6-TG resistant mutant frequencies, respectively, compared to untreated control cells. The cell cycle analyses performed during the expression time (9-12 days) have shown that after 2 and 4h treatment with APC the cells were blocked in G2 phase during the majority of the expression period, compared to control cells. Four days after the treatment, the amount of cells in G2 phase increased about two-fold (28.6-31.8% compared to 13.5% in the untreated cells). The mode of cell death during the expression time was via necrosis, rather than apoptosis, which was demonstrated by fluorescein-diacetate (FDA)-staining and terminal dUTP nick end labeling (TUNEL)-method.