4-AMIDINOINDAN-1-ONE 2'-AMIDINOHYDRAZONE (CGP 48664A) EXERTS IN-VITROGROWTH-INHIBITORY EFFECTS THAT ARE NOT ONLY RELATED TO S-ADENOSYLMETHIONINE DECARBOXYLASE (SAMDC) INHIBITION

The competitive S-adenosylmethionine decarboxylase (SAMdc; EC 4.1.1.50 ) inhibitor 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) inhi bits growth more effectively than the irreversible SAMdc inhibitor )-4 -amino-2-butenyl]methylamino}-5'-deoxyadenosine (AbeAdo), while having similar effects on polyamine contents. We hypothesized that growth in hibition by CGP 48664A is not merely accomplished by SAMdc inhibition. Concentration-related growth inhibitory effects of AbeAdo, CGP 48664A and methylglyoxal bis(guanylhydrazone) (MGBG) were investigated in L1 210 cells that were additionally exposed to 10 mu M AbeAdo. This conce ntration causes maximal growth inhibition, profound SAMdc inhibition a nd plateau polyamine contents. Almost complete inhibition of functiona l SAMdc activity by 10 mu M AbeAdo was confirmed by demonstration of p oor conversion of tetradeuterated spermidine to tetradeuterated spermi ne by gas chromatography-mass spectrometry. Increasing AbeAdo did not affect L1210 cell numbers, viability, nor polyamine contents. MGBG pro ved highly toxic. CGP 48664A did not affect L1210 polyamine contents, but cell numbers and viability decreased dose-dependently to 50% and 7 0% of control, respectively. We conclude that CGP 48664A inhibits L121 0 growth not only through SAMdc inhibition, but also by an as yet poor ly understood second effect with higher IC50. The alleged second effec t of CGP 48664A appears important for its potent antitumor effect.