New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity.
Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.
Regenass
U
U
Research Department, CIBA-GEIGY, Limited, Basel, Switzerland.
Caravatti
G
G
Mett
H
H
Stanek
J
J
Schneider
P
P
Müller
M
M
Matter
A
A
Vertino
P
P
Porter
C W
CW
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism; D007939:Leukemia L1210; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D011073:Polyamines / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D011073:Polyamines; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine