Combination of standard cytotoxic agents with polyamine analogues in the treatment of breast cancer cell lines

Polyamines are essential for cell growth and differentiation. Structural po lyamine analogues have been shown to have antitumor activity in experimenta l models including breast cancer. The ability of polyamine analogues to alt er activity of cytotoxic chemotherapeutic agents in breast cancer models ha s not been evaluated. This study evaluates the ability of two polyamine ana logues, N-1-ethyl-N-11-[(cyclopropyl)methyl]-4,8-diazaundecane (CPENSpm) an d N-1-ethyl-N-11-[(cycloheptyl)methyl]4,8-diazaundecane (CHENSpm) to synerg ize with cytotoxics in five human breast cancer cell lines. Antagonism, add itivity, or synergy of the combinations was determined using the median eff ect/combination index model. The chemotherapeutic agents chosen, cis-diamin echloroplatinum(II), doxorubicin, 5-fluorouracil, fluorodeoxyuridine, 4-hyd roperoxycyclophosphamide, paclitaxel, docetaxel, and vinorelbine, all have antitumor activity in breast cancer and represent a spectrum of mechanisms. Three treatment schedules of polyamine analogue and cytotoxic were tested in MCF-7 and MDA-MB-468 lines, demonstrating a schedule-dependence of syner gistic growth inhibition. Cytotoxic agent alone for 24 h followed by polyam ine analogue alone for 96 h resulted in the most synergistic combinations a nd the greatest synergy. This schedule was then tested in three additional breast cancer lines, and several synergistic combinations were again identi fied. Two cytotoxics, vinorelbine and the fluoropyrimidines, showed the mos t promise in combination with the polyamine analogues. They were able to sy nergize with one or both polyamine analogues in most of the breast cancer c ell lines. CPENSpm was also able to synergize with virtually all of the cyt otoxics in the estrogen receptor cy-positive MCF-7 and T-47D lines. These p reclinical data demonstrate a treatment schedule and combinations of polyam ine analogues and cytotoxics that will be important to study mechanisticall y and clinically for breast cancer.