Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor
| Autor: | David S. Alberts, Sydney E. Salmon, Katerina Dvorakova, G. Robert Pettit, Robert T. Dorr, Kristi Snead |
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| Rok vydání: | 1996 |
| Předmět: |
Male
Pharmacology Biology Phosphates chemistry.chemical_compound Mice In vivo Tubulin Neoplasms Stilbenes Tumor Cells Cultured Animals Humans Pharmacology (medical) IC50 Chromatography High Pressure Liquid Combretastatin Albumin Blood proteins Antineoplastic Agents Phytogenic In vitro Tubulin Modulators Neoplasm Proteins Mice Inbred C57BL Oncology chemistry Paclitaxel Mice Inbred DBA Immunology Cattle Drug Screening Assays Antitumor Fetal bovine serum Cell Division Protein Binding |
| Zdroj: | Investigational new drugs. 14(2) |
| ISSN: | 0167-6997 |
| Popis: | 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 micrograms/mL for a 1-hour exposure (n = 35 specimens) and 0.27 microgramf1p4for 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 micrograms/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 (or = 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/B1 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. |
| Databáze: | OpenAIRE |
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