Combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines.
Estramustine (EM) and taxol, two antimicrotubule agents with distinct and apparently opposing mechanisms of action, were found to be effective in combination in the preclinical treatment of EM-resistant and sensitive, wild-type human prostatic carcinoma cell lines. Estramustine combined with 1 nM taxol (concentration 100-fold less than that measured in plasma of patients treated with taxol) produced greater than additive effects on the inhibition of cell survival of both wild-type and EM-resistant cells. When taxol was used with another microtubule-destabilizing drug, vinblastine, no significantly increased cytotoxicity was observed. Other effects on wild-type and EM-resistant cells produced by the combination of EM and taxol included (a) an increased proportion of the cells in the S phase of the cell cycle; (b) no mitotic block; and (c) an increase in the percentage of micronucleated cells from a control value of less than 1% to greater than 20% after drug treatment. Immunofluorescent microscopic analysis of the effect of this drug combination on the mitotic spindle apparatus revealed specific examples of aberrant mitotic figures, including multiple asters, cells with two distinct spindles, and tripolar spindles able to traverse mitosis and complete cytokinesis. These data provide supportive preclinical evidence for the potential development of an EM/taxol combination clinical regimen either for prostate or other cancers.
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
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Speicher
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Tew
D000470:Alkaloids / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000648:ultrastructure; D002453:Cell Cycle / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004961:Estramustine / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D015162:Micronucleus Tests; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D017239:Paclitaxel; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000648:ultrastructure; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D004961:Estramustine; D017239:Paclitaxel