Augmentation of vincristine cytotoxicity by megestrol acetate |
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Authors: | Sualp Tansan Yener Koç Hayri Aydin Godofredo Urbano R McCaffrey |
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Institution: | (1) Section of Hematology/Oncology, Evans Memorial Department of Research, Boston University Medical Center, The University Hospital, 88 East Newton Street, E-556, Boston, MA 02118, USA Tel. (617) 638 7520; Fax (617) 638 7536, US |
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Abstract: | Purpose: To determine the effect of a semisynthetic progesterone, megestrol acetate (MA), on the cytotoxicity of various chemotherapeutic
agents including vincristine, doxorubicin, actinomycin-D, taxol, vinblastine and colchicine in cell lines with or without
P-gp expression. Methods: Three cell lines with high P-gp expression (two colon cancer and one leukemia), and a control cell line with no P-gp expression
were exposed to chemotherapeutic agents in the presence or absence of MA and drug sensitivity was determined using the MTT
colorimetric assay. P-gp-170 expression was detected by flow cytometry using JSB-1 monoclonal antibody and the functionality
of MDR expression was tested by rhodamine-123 uptake studies. In vitro drug accumulation studies were performed using 3H]-vincristine. The results were subjected to paired t-test analysis and 95% confidence intervals were determined in cytotoxicity tests. Results: MA augmented the cytotoxicity of vincristine, but not doxorubicin, actinomycin-D, taxol, vinblastine or colchicine in the
three P-gp-expressing cell lines, whereas verapamil augmented the cytotoxicity of doxorubicin and vincristine. MA did not
augment the cytotoxicity of vincristine in the P-gp-negative HUT-102 cell line. Conclusion: MA augmented vincristine cytotoxicity in P-gp-expressing cell lines. However, this phenomenon did not occur with the other
classic MDR drugs. Therefore, the augmentation of vincristine cytotoxicity by MA can be explained either by involvement of
a different mechanism that coexists with the mdr-1 phenotype or by the presence of a different affinity or binding site on
the P-gp molecule for MA compared to that for the other classic MDR drugs and verapamil.
Received: 8 September 1995 / Accepted: 3 June 1996 |
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Keywords: | Vincristine Megestrol acetate Cytotoxicity Multidrug resistance |
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