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Current Studies with Methylglyoxal-Bis(Guanylhydrazone) *

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Current Studies with Methylglyoxal-Bis(Guanylhydrazone) * Current Studies with Methylglyoxal-bis(guanylhydrazone) * ENRICO MIHIcH (Department of Experimental Therapeulies, Roswell Park Memorid Institute, New York State Department of Health, Buffalo, New York) SUMMARY 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 liven 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 in hibition 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 main tamed provided that the structures contain two unsubstituted symmetric guanidine moieties. The regression of Sarcoma 180 in pynidoxine-deficient IIaICR Swiss mice and the allogenic rejection of skin grafts exchanged between AKR and CS7BL/6 mice are antagonized by the drug. The effects of methylglyoxal-bis(guanylhydnazone) against leukemia L1@10 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. The clinical activity of methylglyoxal-bis hydroxymethylglyoxal derivatives was reported (guanyihydrazone) (CH@-G) against acute myelo initially by Freedlander and French (8, 9). In addi cytic leukemia (11), some lymphomatous diseases, tion, these authors reported that the three con and tumors of the head and neck region (10, 3@, geners inhibited the growth of Adenocarcinoma 33), as well as the remarkable hypoglycemia in 755 but were ineffective against Sarcoma 180 and duced in several species (@7,38), make of this corn neuroblastoma C-1300; CHrG was the most pound a drug of considerable pharmacological active compound of the series against leukemia interest. L1@10,whereasthe hydroxymethylglyoxal deny Evidence for the activity of CHr.G and related ative was the most effective against Adenocarcino compounds against several transplantable tumors ma 755 (8, 9). The activity of glyoxal-bis(guanyl is substantial. The significant prolongation of sur hydrazone) against leukemia L1@10 was confirmed vival time of mice beaning leukemia L1@10 result by Oettgen and Burchenal (@8). These authors ing from the dietary administration of glyoxal-bis also reported that the compound was effective (guanylhydrazone) and the methylglyoxal or against leukemias B-8@-T and P-815, but only slightly active or inactive against leukemias P1354 S This investigation was supported in part by a research grant (CA-04130) from the National Cancer Institute, United and P1081, respectively (@8). In addition, CHs-G States Public Health Service. was found to be effective against Sarcoma 180 1375 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1963 American Association for Cancer Research. 1376 Cancer Research Vol. @3,September 1963 ascites but inactive, at nontoxic doses, against modes of administration were in the same range in leukemia L4946 and several other experimental mice and rats. The LD50 after five daily intraperi tumors (14). toneal injections was 1@3mg/kg in Swiss mice and Two pharmacological characteristics became 88 mg/kg in Spraguo-Dawley rats weighing about apparent during the early chemotherapeutic 100 gm. When daily intravenous injections were studies—namely, the relatively poor absorption of continued for 14 days, the LD50 was between 15 the compounds by the oral route and their narrow and @0mg/kg in dogs, whereas repeated intra therapeutic range of dosage. Prolongation of sun venous administration of 10 mg/kg caused death vival time of leukemic mice was achieved by die of monkeys within 14—@4days. Even when differ tary administration of the sulfate salt of CHs-G at ences are taken into account in the mode of ad concentrations ranging from 0.1@ to 0.5 pen cent ministration in various species, it seems reasonable corresponding to a daily intake of approximately to conclude that, quantitatively, CHrG is more @50and1000 mg/kg, respectively. Doubling of the toxic in dogs and monkeys than in rodents. survival time of DBA2 mice beaning leukemia The greater toxicity of CHrG after parenteral L1@10wasobserved in our laboratory after dietary than after oral administration observed in mice treatment with the dihydrochlonide salt of CHrG (8, 9, 14, @8)was confirmed during the toxicologi at concentrations as low as 0.06 pen cent, corre cal evaluation in rodents and dogs (@7) and in the sponding to a daily dose of about 1@0 mg/kg. In initial clinical trials (3@). In rats, for instance, the contrast, intrapenitoneal injections of only @5—50toxicity of intnapenitoneal and oral administra mg/kg of CIL-G caused effects comparable to tions differed by a factor of 8 and 3 after single those obtained with the dietary doses mentioned and five repeated treatments, respectively. In dogs (14). Indeed, parenteral administrations of 90—150 lethal doses after repeated administration by the mg/kg of CHrG are toxic in DBA2 mice. two routes differed by a factor of ca. 5. In man, Increases of the optimal intrapenitoneal dose by oral administration had no activity other than a @ less than a factor of decreased survival time as a strong cathartic effect; in addition, spectrophoto result of toxicity (14). The somewhat narrower metric assay of blood levels of CHrG showed that, range of therapeutic activity by parenteral than by in both rats and humans, the drug was poorly ab dietary administration is probably the result of sorbed from the gastrointestinal tract (Holland, slow drug absorption from the gastrointestinal unpublished data). tract. Freedlanden and French had noted that The toxicity curve was very steep after paren dietary treatment with this group of drugs was teral treatments. For instance, in rats given five most effective in their experiments (9). daily intrapenitoneal injections, the LD50 was 88 The glyoxal-bis(guanylhydrazone) derivatives mg/kg, with 19/@0 confidence limits ranging from elicited considerable interest mainly because of 83 to 93 mg/kg and a slope of 1.15 when calcula their outstanding activity against leukemia L1@10 tions were made according to Litchfield and Wil and because of the novelty of their chemical struc coxon (17). Moreover, two dogs did not die after tune in cancer chemotherapy. The recognition that a single intravenous injection of 40 mg/kg of these compounds did warrant further study and CHrG (Mihich, unpublished data), whereas five possibly clinical trial prompted their toxicological out of seven died after 50 mg/kg. This sharp in evaluation in animals. crease in toxicity by small increments of dosage must be viewed in relation to the narrow range of TOXICOLOGY OF METHYLGLYOXAL doses causing optimal antileukemic effects in mice BIS(GUANYLHYDRAZONE) (14). The combination of these two sets of data The toxicological study of CHrG was per conditions the presumption that the range of thera formed initially in our laboratory with mice, rats, peutically selective dosage in man may be rather rabbits, and dogs (@5, @7)and more recently by narrow. Clinical data obtained to date seem to Tidball and Rall with monkeys (38). The detailed substantiate this prediction (33). Indeed, thena description of the toxicological effects has been peutic effects in man were obtained with doses of presented. Only the most important toxicological 4—10mg/kg at the cost of severe toxicity (11, aspects will be discussed here, with particular 33). reference to the initial clinical findings and to the A final point concerning the quantitative toxi questions that current unpublished studies at cology data is that CHrG did not show significant tempt to answer. Only results obtained with the cumulative toxicity upon repeated parenteral ad soluble dihydrochlonide on diacetate salts of ministrations. Thus, in Swiss mice, the LD50 by CH@-Gwillbe considered. single and five repeated intrapenitoneal injections The lethal doses of CHrG by corresponding was 120 and 1@3 mg/kg, respectively, whereas in Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1963 American Association for Cancer Research. M1HIcH—Methylglyoxal-bis(guanylhydrazone) 1377 rats corresponding doses were 10@and 88 mg/kg. been clearly answered. The occasional presence of In dogs, total intravenous doses of 140 or @10mg/ cytoplasmic inclusions in lungs and in other tissues kg were not lethal when fractionated into fourteen suggested the possibility that CHrG may condi daily administrations, whereas single injections of tion the development of an atypical distemper in 60 or 75 mg/kg were lethal in each case. These the intoxicated animals, despite their previous observations suggest that in rodents, and to a immunization. Preliminary data indicated, how lesser extent in dogs, CH@-G may be rapidly neu even, that titers of antibodies against distemper tralized or excreted. In rats, however, available were within the normal range in two dogs intoxi evidence suggests that, within the LD,0 range, cated with fourteen daily intravenous injections much of the hepatic insult may be elicited by the of @0mg/kg of CH@-G. The characteristic intra first dose. Since liver damage seems to be respon nuclear bodies did not react with the Feulgen sible for death in the majority of the rats, the con stain. tribution of subsequent injections to the lethal Marked lymphoid depression was observed in outcome may be comparatively minor.
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