Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs.

摘要: Recent preclinical studies have shown that frequent administration in vivo of low doses chemotherapeutic drugs (“metronomic” dosing) can affect tumor endothelium and inhibit angiogenesis, reducing significant side effects (e.g., myelosuppression) involving other tissues, even after chronic treatment. This suggests activated endothelial cells may be more sensitive, or selectively to protracted (“high-time”) low-dose chemotherapy compared with types normal cells, thus creating a potential therapeutic window. To examine this hypothesis, we assessed the several different drugs—namely paclitaxel, 4-hydroperoxycyclophosphamide, BMS-275183 (an oral taxane), doxorubicin, epothilone B (EpoB) its analogue 5-methylpyridine EpoB—on human microvascular macrovascular fibroblasts, drug-sensitive multidrug-resistant breast cancer cell lines culture, using both short-term (24 h) versus long-term (144 h), continuous exposures, where drug-containing medium was replaced every 24 h. Whereas little differential only weak were observed exposure, striking trend comparative vascular hypersensitivity induced exposure protocol. Potent growth inhibition as well induction apoptosis IC50 values range 25–143 pm for BMS-275183, EpoB, 5-methylpyridine-EpoB. In contrast, fibroblasts tested 500 >1 nm these drugs. Similar noted 4-hydroperoxycyclophosphamide. The results are consistent possibility therapy various highly selective effect against cycling relevant use certain an optimal way delivering antiangiogenic therapy.