Cellular pharmacodynamics of the cytotoxic guanidino-containing drug CHS 828. Comparison with methylglyoxal-bis(guanylhydrazone).
N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N"-4-pyridylguanidine (CHS 828) is a new guanidino-containing compound with antitumoral activity both in vitro and in vivo. Its activity profile differs from those of standard cytotoxic drugs but the mechanism of action is not yet fully understood. CHS 828 is 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 to another compound containing two guanidino groups, methylglyoxal-bis(guanylhydrazone) (MGBG). MGBG is known to inhibit the synthesis of polyamines, which are important in, e.g., proliferation and macromolecular synthesis. The concentration-response relationship of CHS 828 closely resembled that of MGBG and the drugs were similar with respect to inhibition of DNA and protein synthesis. On the other hand, CHS 828 induced a significant increase in cellular metabolism while MGBG did not. The cytotoxic effect of MGBG was reversed by the addition of exogenous polyamines, while that of CHS 828 was unaffected. Unlike MGBG, there was also no effect of CHS 828 on the levels of decarboxylating enzymes in the polyamine biosynthesis. In conclusion, CHS 828 does not appear to share any major mechanisms of action with the polyamine synthesis inhibitor MGBG. Further studies will be required to define the exact mechanism of action of CHS 828.
Ekelund
S
S
Department of Medical Sciences, Division of Clinical Pharmacology, University Hospital, S-751 85, Uppsala, Sweden. Sara.Ekelund@medsci.uu.se
Sjöholm
A
A
Nygren
P
P
Binderup
L
L
Larsson
R
R
D000970:Antineoplastic Agents / Q000633:toxicity*; D002262:Carboxy-Lyases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003486:Cyanides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005470:Fluorometry; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008935:Mitoguazone / Q000633:toxicity*; D014176:Protein Biosynthesis; D013095:Spermidine / Q000096:biosynthesis / Q000494:pharmacology; D020298:U937 Cells
D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D004247:DNA; D002262:Carboxy-Lyases; D008935:Mitoguazone; D013095:Spermidine