• Polyamine analogues in anticancer drug design

      Li, Yanlong; Callery, Patrick S. (1996)
      The binding affinity of polyamines toward DNA makes polyamine analogues a potential source of new anticancer agents that can interact selectively with DNA. Moreover, the presence of an active polyamine transport system in tumor cells may offer additional selectivity of these polyamine analogues toward tumor cells. Based on this rationale, a group of alkylating spermine analogues, including a diaziridinylspermine (BAS), two methylated analogues of BAS, and a norspermine analogue of BAS, was designed, synthesized and assessed for their biological activities. Cytotoxicity induced by BAS was demonstrated to be associated both with the alkylating functional group, aziridine, and also with the polyamine backbone structure. These analogues degraded or cross-linked DNA at a concentration that was 1000-fold lower than that of L-phenylalanine nitrogen mustard (LPAM). Transport studies were carried out by determining the competitive inhibition by synthesized polyamine analogues of (3H) -spermidine uptake in L1210 murine leukemia cells. Comparative molecular field analysis (CoMFA) was used to extract information on the structural requirements of inhibitors of the polyamine transport system. BAS and three BAS analogues were predicted to be substrates of the polyamine transporter. In vivo studies were carried out in a murine L1210 model in female {dollar}\rm CD\sb2F\sb1{dollar} mice. BAS increased survival of mice implanted with L1210 cells longer than did thiotepa, a clinically effective anticancer drug, when the same dose schedule was applied. Preliminary in vivo studies in a human non-small cell lung tumor H522 model also showed that BAS was effective in reducing, or at least controlling, solid tumor growth. Further design efforts were focused on reducing the nonspecific toxic effects of BAS. It was found that methylated analogues of BAS and the norspermine analogue of BAS were more than ten times less toxic to mice than was BAS. The observation of in vivo activity against implanted L1210 cells suggests that BAS can be used as a lead compound in anticancer drug design.