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Combination of Standard Cytotoxic Agents with Polyamine Analogues in the Treatment of Breast Cancer Cell Lines¹

The Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, Maryland 21231 [H. A. H., V. R. D., K. A. B., W. L. D., R. A. C., N. E. D.], and Wayne State University, Detroit, Michigan 48202 [P. M. W.]

Polyamines are essential for cell growth and differentiation. Structural polyamine analogues have been shown to have antitumor activity in experimental models including breast cancer. The ability of polyamine analogues to alter activity of cytotoxic chemotherapeutic agents in breast cancer models has not been evaluated. This study evaluates the ability of two polyamine analogues, 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. Antagonism, additivity, or synergy of the combinations was determined using the median effect/combination index model. The chemotherapeutic agents chosen, cisdiaminechloroplatinum(II), doxorubicin, 5-fluorouracil, fluorodeoxyuridine, 4-hydroperoxycyclophosphamide, 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 synergistic growth inhibition. Cytotoxic agent alone for 24 h followed by polyamine analogue alone for 96 h resulted in the most synergistic combinations and the greatest synergy. This schedule was then tested in three additional breast cancer lines, and several synergistic combinations were again identified. Two cytotoxics, vinorelbine and the fluoropyrimidines, showed the most promise in combination with the polyamine analogues. They were able to synergize with one or both polyamine analogues in most of the breast cancer cell lines. CPENSpm was also able to synergize with virtually all of the cytotoxics in the estrogen receptor -positive MCF-7 and T-47D lines. These preclinical data demonstrate a treatment schedule and combinations of polyamine analogues and cytotoxics that will be important to study mechanistically and clinically for breast cancer.

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