Synergism of the polyamine analogue, N1,N11-bisethylnorspermine with cis-diaminedichloroplatinum(II) against murine neoplastic cell lines in vitro and in vivo

The activities of naturally occurring polyamines are exploited to enhance the antitumor activity of cisplatin. The polyamine analogue, N1,N11-bis-ethylnorspermine (BE-3-3-3) is used at subtherapeutic levels in L1210 leukemia suspension cultures and plating efficiency assays of B16 F1 melanoma cells to increase the cytotoxic effect of cisplatin seven and tenfold, respectively. Similar experiments in mice reveal additive effects for DBA/2J mice bearing L1210 and synergistic effects in C57/B6 mice bearing B16 F1 tumor after optimizing combination ratios. In the latter model, at a BE-3-3-3/cisplatin molar ratio of 250:1, an increased lifespan (ILS) of 56% is recorded during a 9-day dosing schedule, whereas BE-3-3-3 at the same dose caused a 21% ILS, and cisplatin only exhibited a 7% ILS. Possible reasons for differences between in vitro and in vivo activity are discussed.