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 anal ogue, has been shown to be clinically effective against advanced breast can cer. In this report, the combined effect of NVB with medroxyprogesterone ac etate (MPA), a synthetic progesterone derivative, was examined in vitro aga inst human breast carcinoma MCF-7 cells. The combined effect was demonstrat ed 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 G(1)-phase accumulation as well as the inducti on of cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1) protein and th e dephosphorylated form of retinoblastoma protein (pRb). In contrast, MPA a t 0.1 mu M also induced G(1)-phase accumulation as well as the reduced expr ession of cyclin D1 protein. In addition, the combination of both drugs ind uced augmented G(1)-phase accumulation, which occurred along with p21(WAF1/ CIP1) protein induction, cyclin D1 protein reduction and pRb dephosphorylat ion. These results demonstrate that the synergistic combined effect of NVB with MPA was mediated through enhancement of G(1)-phase accumulation that r esulted from the different action point(s) of each drug. Furthermore, the s ynergistic 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 sugg est that combination therapy of NVB with MPA in breast cancer might be effe ctive in clinical studies.