Cellular pharmacodynamics of the cytotoxic guanidino-containing drug CHS 828. Comparison with methylglyoxal-bis(guanplhydrazone)

N-(6-(4-chlorophenoxy)hexyl)-N ' -cyano-N " -4-pyridylguanidine (CHS 828) i s a new guanidino-containing compound with antitumoral activity both in vit ro and in vivo. Its activity profile differs from those of standard cytotox ic drugs but the mechanism of action is not yet fully understood. CHS 828 i s presently in early phase I and II clinical trials. In the present study, the pharmacodynamic effects at the cellular level of CHS 828 was compared t o another compound containing two guanidino groups, methylglyoxal-bis(guany lhydrazone) (MGBG). MGBG is known to inhibit the synthesis of polyamines, w hich are important in, e.g., proliferation and macromolecular synthesis. Th e concentration-response relationship of CHS 828 closely resembled that of MGBG and the drugs were similar with respect to inhibition of DNA and prote in synthesis. On the other hand. CHS 828 induced a significant increase in cellular metabolism while MGBG did not. The cytotoxic effect of MGBG was re versed by the addition of exogenous polyamines, while that of CHS 828 was u naffected. Unlike MGBG, there was also no effect of CHS 828 on the levels o f decarboxylating enzymes in the polyamine biosynthesis. In conclusion CHS 828 does not appear to sharp any major mechanisms of action with the polyam ine synthesis inhibitor MGBG. Further studies will be required to define th e exact mechanism of action of CHS 828. (C) 2001 Elsevier Science B.V. All rights reserved.