Recently methylglyoxal-bis(guanylhydrazone) elicited considerable interest as an anticancer agent in view of its clinical activity against acute myelocytic leukemia and lymphomatous diseases. The antitumor and toxicological effects of this compound and current pharmacological investigations carried out in this laboratory are reviewed in the present report. The delayed hypoglycemia induced by the drug in rabbits is associated with hepatic necrosis and becomes evident only after depletion of hepatic glycogen. Following administration of glucose or galactose, deposition of glycogen in the liver is inhibited as early as 4 hours after treatment with the drug at a time when hepatic necrosis is not yet histologically evident. The possibility is discussed that inhibition of oxidative phosphorylation by the drug may be related to the hypoglycemia observed. The comparative study of the antitumor and hypoglycemic activity of several closely related analogs of methylglyoxal-bis(guanylhydrazone) revealed that minor modifications in the chemical structure of the parent compound greatly diminish the antitumor potency of the derivative. In contrast, the hypoglycemic effect is maintained provided that the structures contain two unsubstituted symmetric guanidine moieties.

The regression of Sarcoma 180 in pyridoxine-deficient HaICR Swiss mice and the allogenic rejection of skin grafts exchanged between AKR and C57BL/6 mice are antagonized by the drug. The effects of methylglyoxal-bis(guanylhydrazone) against leukemia L1210 are prevented by the concurrent administration of spermidine by the same or a different route. The data available are discussed in relation to the possible mechanisms of action of this new antitumor agent.


This investigation was supported in part by a research grant (CA-04130) from the National Cancer Institute, United States Public Health Service.

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