Effect of Protein Kinase C Modulation with Bryostatin 1 on Paclitaxel-Induced Growth Inhibition and Apoptosis in Human Breast Cancer

摘要

Polyamines are essential for cell growth and differentiation. Structural polyamine analogs have been shown to have anti-tumor activity in experimental models including breast cancer. This study evaluates the ability of two polyamine analogs, N1-ethyl-N11- ((cyclopropyl)methyl) -4,8-diazaundecane (CPENSpm) and N1-ethyl-N11- ((cycloheptyl)methyl) 4,8-diazaundecane (CHENSpm) to synergize with cytotoxics in five human breast cancer cell lines. The chemotherapeutic agents chosen, cis- diaminechloroplatinum (II), doxorubicin, 5- fluorouracil, fluorodeoxyuridine, 4- hydroperoxycyclophosphamide, paclitaxel, docetaxel, and vinorelbine, all have anti-tumor activity in breast cancer and represent a spectrum of mechanisms. Three treatment schedules of polyamine analog and cytotoxic were tested in MCF-7 and MDA-MB-468 lines. Cytotoxic agent alone for 24 hours followed by polyamine analog alone for 96 hours resulted in the most synergistic combinations and the greatest synergy. Two cytotoxics, vinorelbine and the fluoropyrimidines, showed the most promise in combination with the polyamine analogs. They were able to synergize with one or both polyamine analogs in most of the breast cancer cell lines. CPENSpm was also able to synergize with virtually all cytotoxics in the estrogen receptor positive MCF-7 and T47D lines. These preclinical data demonstrate a treatment schedule and combinations of polyamine analogs and cytotoxics that will be important to study mechanistically and clinically for breast cancer.