Abstract
Recent preclinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs (“metronomic” dosing) can affect tumor endothelium and inhibit tumor angiogenesis, reducing significant side effects (e.g., myelosuppression) involving other tissues, even after chronic treatment. This suggests that activated endothelial cells may be more sensitive, or even selectively sensitive, to protracted (“high-time”) low-dose chemotherapy compared with other types of normal cells, thus creating a potential therapeutic window. To examine this hypothesis, we assessed the effects of several different chemotherapeutic drugs—namely paclitaxel, 4-hydroperoxycyclophosphamide, BMS-275183 (an oral taxane), doxorubicin, epothilone B (EpoB) and its analogue 5-methylpyridine EpoB—on human microvascular or macrovascular endothelial cells, fibroblasts, and drug-sensitive or multidrug-resistant breast cancer cell lines in cell 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 and only weak effects were observed using the short-term exposure, a striking trend of comparative vascular endothelial cell hypersensitivity was induced using the continuous long-term exposure protocol. Potent differential growth inhibition effects as well as induction of apoptosis were observed with IC50 values in the range of 25–143 pm for paclitaxel, BMS-275183, EpoB, and 5-methylpyridine-EpoB. In contrast, the IC50 values for tumor cells and fibroblasts tested were in the range of 500 pm to >1 nm for these drugs. Similar differential IC50 values were noted using 4-hydroperoxycyclophosphamide. The results are consistent with the possibility that continuous low-dose therapy with various chemotherapeutic drugs may have a highly selective effect against cycling vascular endothelial cells, and may be relevant to the use of continuous or frequent administration of low doses of certain types of drugs as an optimal way of delivering antiangiogenic therapy.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by a grant from the NIH Service (CA41223; to R. S. K.). G. B. is financially supported by the Italian Society of Pharmacology and by an international scholarship of the Interdepartmental Centre of Clinical Pharmacology and Experimental Therapeutics, University of Pisa, generously donated by the Ente Cassa di Risparmio di Lucca.
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↵2 To whom requests for reprints should be addressed, at Sunnybrook and Women’s College Health Sciences Centre, Molecular and Cell Biology Research, S-218, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada. Phone: (416) 480-5711; Fax: (416) 480-5703; E-mail: robert.kerbel{at}swchsc.on.ca
- Received July 12, 2002.
- Accepted September 27, 2002.
- ©2002 American Association for Cancer Research.