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, cis-diaminechloroplatinum(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 alpha-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.