Augmentation of vincristine cytotoxicity by megestrol acetate

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.

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.

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.

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.