RESUMEN
Camptothecin-20(s)-O-(2-pyrazolyl-1)acetic ester (CPT6) is a novel semi-synthetic analog of camptothecin. In a previous report, CPT6 possessed higher cytotoxic activity in vitro towards human breast tumor MCF-7 cells than topotecan. In this study, the antitumor activity of CPT6 on the human breast tumor MCF-7 cell line was analyzed using the MTT method. The underlying mechanism of CPT6 action was investigated by analyzing the cell cycle distribution, apoptotic proportion, changes in mitochondrial membrane potential, and intracellular Ca2+ concentration using flow cytometry. Nuclear and mitochondrial morphologies were also observed by laser scanning confocal and transmission electron microscopy. DNA damage was observed in MCF-7 cells treated with CPT6. Low-dose CPT6 had a significant cytotoxic effect and could inhibit proliferation and induce apoptosis in MCF-7 cells, possibly through cell nucleus fragmentation and DNA damage. CPT6 thus appears to display potent antitumor activity against human breast tumor MCF-7 cells via the induction of apoptosis, and may be a useful alternative drug for breast cancer therapy.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/farmacología , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Camptotecina/análogos & derivados , Ciclo Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/ultraestructura , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Topotecan/farmacologíaRESUMEN
In an effort to decrease the toxicity of camptothecin (CPT) and improve selectivity for hepatoma and colon cancer cells, bile acid groups were introduced into the CPT 20 or 10 positions, resulting in the preparation of sixteen novel CPT-bile acid analogues. The compounds in which a bile acid group was introduced at the 20-hydroxyl group of CPT showed better cytotoxic selectivity for human hepatoma and colon cancer cells than for human breast cancer cells. Fluorescence microscopy analysis demonstrated that one compound (E2) entered human hepatoma cells more effectively than it did human breast cancer cells. Compound G4 exhibited the best anti-tumour activity in vivo. These results suggested that introduction of a bile acid group at the 20-position of CPT could decrease toxicity in vivo and improve selectivity for hepatoma cells.