Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor |
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Authors: | Robert T. Dorr Katerina Dvorakova Kristi Snead David S. Alberts Sydney E. Salmon G. Robert Pettit |
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Affiliation: | (1) Department of Pharmacology, The University of Arizona, Tucson, AZ, USA;(2) Department of Medicine, The University of Arizona, Tucson, AZ, USA;(3) The Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA;(4) College of Medicine and College of Nursing, The University of Arizona, Tucson, AZ, USA;(5) The Cancer Research Institute, Department of Chemistry, Arizona State University, Tempe, AZ, USA;(6) Arizona Cancer Center, 1515 N. Campbell Avenue, 85724 Tucson, AZ, USA |
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Abstract: | Summary The tubulin-binding natural product combretastatin A-4 (CA-4) was tested for antitumor activity against fresh human tumors in vitro and 2 mouse tumors, both in vitro and in vivo. In colony forming assays using 10% fetal bovine serum, CA-4 was inhibitory in 27/40 human ovary cancers with a mean IC50 of 3.18 g/mL for a 1-hour exposure (n = 35 specimens) and 0.27 g/mL for a continuous exposure to CA-4 for 11–14 days (n = 5 specimens). Murine B-16 melanoma and P-388 leukemia were also highly sensitive to CA-4 in vitro with an identical IC50 value of 0.0007 g/mL for continuous drug exposure for 8 days. Comparable in vitro cell culture studies performed in serum concentrations higher than 10%, revealed a significant loss of cytotoxic potency. Using the same reversed-phase HPLC technique as developed for paclitaxel, CA-4 was shown to bind to serum proteins (30,000 mw) > 99% and to albumin approximately 70%. CA-4 was only marginally active (25% increased lifespan) in DBA/2 mice bearing P-388 leukemia who were given doses of 100 mg/kg IP on either days, 1, 5 and 9 (p = 0.075 by Wilcoxon analysis) or on consecutive days 1–9 (p = 0.19 compared to control). A higher IP dose of 150 mg/kg on days 1, 5 and 9 did not delay subcutaneous B-16 melanoma tumor growth in C57/Bl mice. These findings demonstrate a substantial loss of antitumor efficacy for CA-4 in physiologic serum concentrations in vitro. No consistent antitumor activity was observed in two murine tumor models in vivo. |
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Keywords: | antitumor agent protein binding microtubule inhibition combretastatin |
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