Adenocarcinoma of the pancreas presents a formidable challenge both experimentally and clinically, whereby effective anticancer therapy is lacking. We have recently explored a relatively new class of antitumor agents in pancreatic cancer cell lines and have found the bis-ethyl derivatives of spermine to show considerable promise. In the present paper, we report the results of in vivo studies demonstrating the antitumor activity of two of these N-alkylated analogues, N1,N14-bis(ethyl)homospermine (BEHSPM) and N1,N11-bis(ethyl)norspermine (BENSPM) in athymic (nude) mouse xenografts of two human pancreatic ductal adenocarcinoma cell lines, PANC-1 (poorly differentiated) and BxPC-3 (moderately well-differentiated). BENSPM was found to exert greater antitumor activity in vivo than either BEHSPM or other conventional agents, largely because higher doses could be given due to its lower toxicity to mice. BENSPM shows greater activity than any other agent we have thus far tested against our pancreatic-cancer models. Optimal schedules of administration have yet to be determined. Nevertheless, of the analogues tested, BENSPM presently appears to be the analogue of choice for further development.