Combined effect of navelbine with medroxyprogesterone acetate against human breast carcinoma MCF-7 cells in vitro.

Navelbine (NVB, vinorelbine ditartrate, KW-2307), a new vinca alkaloid analogue, has been shown to be clinically effective against advanced breast cancer. In this report, the combined effect of NVB with medroxyprogesterone acetate (MPA), a synthetic progesterone derivative, was examined in vitro against human breast carcinoma MCF-7 cells. The combined effect was demonstrated to be synergistic using the isobologram and median-effect plot analyses. To elucidate the mechanism of action, we further examined effects of both drugs on cell cycle distribution of the cells in combination and/or alone. NVB at 2 nM induced apparent G1-phase accumulation as well as the induction of cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1) protein and the dephosphorylated form of retinoblastoma protein (pRb). In contrast, MPA at 0.1 microM also induced G1-phase accumulation as well as the reduced expression of cyclin D1 protein. In addition, the combination of both drugs induced augmented G1-phase accumulation, which occurred along with p21(WAF1/CIP1) protein induction, cyclin D1 protein reduction and pRb dephosphorylation. These results demonstrate that the synergistic combined effect of NVB with MPA was mediated through enhancement of G1-phase accumulation that resulted from the different action point(s) of each drug. Furthermore, the synergistic combined effect of NVB with MPA was also observed in other human breast carcinoma cell lines, such as T-47D and ZR-75-1. These results suggest that combination therapy of NVB with MPA in breast cancer might be effective in clinical studies.