Antitumor activities of newly synthesized 5-carbamoyl-1 H-imidazol-4yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4yl piperonylate.
In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.
177 TWO DISTINCT TARGET SITES ON IMP DEHYDROGENASE IN CHEMOTHERAPY
The inhibitory mechanisms of ribavirin 5′-monophosphate, (RMP), SM-108 nucleotide (bredinin 5′-monophosphate, BMP) and thiazole-4-carboxamide adenine dinucleotide (TAD), the active forms of the antimetabolites, ribavirin, SM-108 and tiazofurin, were studied in IMP dehydrogenase purified to homogeneity from rat hepatoma 3924A. RMP and BMP as well as XMP inhibited competitively with IMP and noncompetitively with NAD+. The inhibition by TAD was similar to that of NADU: uncompetitive with IMP and mixed type with NAD+. Ki values for RMP (0.8 uM), BMP (0.11 uM) and TAD (0.13 uM) were markedly lower than those for XMP (136 uM) and NADH (210 uM), and also the Km for IMP (23 uM) and NAD (65 uM). Thus, the drugs interact with IMP dehydrogenase with higher affinities than the natural metabolites, RMP or BMP with IMP-XMP and TAD with NADH site. Preincubation of the purified enzyme with RMP enhanced its inhibitory effect in a time-dependent manner. The enzyme was protected from inactivation by IMP or XMP but not by NAD or NADH. Ribavirin and tiazofurin together provided synergistic killing of hepatoma cells in clonogenic assays and the metabolic flux of de novo guanylate synthesis was also synergistically inhibited. The results provide a biochemical basis for combination chemotherapy with tiazofurin and ribavirin against the 2 different ligand sites of IMP dehydrogenase. (Supported by Outstanding Investigator Grant CA-42510 to G.W.)
5-Fluorocytosine in the Treatment of Experimental Candidiasis in Immunosuppressed Mice
A model infection with Candida albicans was established in mice. The animals were pretreated for 1 week with azathioprine, given dexamethasone, and then infected intravenously with Candida. Mortality for the group given Candida infection alone was 20%, 38% when azathioprine was added, and 50% when dexamethasone and azathioprine were given with infection. The titers of Candida in most mice were 106 per gram of kidney. The rest of the mice were killed at 30 days. At this time, 16% had no evidence of Candida in the kidneys, but 40% of the mice had titers of 106 or more. Mice treated with 5-fluorocytosine had a mortality of less than 4% in 30 days. Five percent of the treated mice killed at 30 days had titers of Candida of 106. Therefore, 5-fluorocytosine increases survival in the presence of continued therapy with azathioprine with or without pretreatment with dexamethasone. The survival is associated with decreased titers of Candida in the kidneys.