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.
Mechanism of action of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide in mammalian cells in culture.
Abstract 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (DIC) is more lethal to Chinese hamster ovary cells and human malignant melanoma cells in culture in the presence than in the absence of light. Incubation of either cell line with DIC labeled at the side chain methyl groups with 14 C resulted in the association of radioactivity with DNA only if light was absent. However, with ring-labeled DIC-2- 14 C, radioactivity was found in both DNA and RNA fractions regardless of the presence or absence of light during incubation. These results are essentially consistent with the current consensus regarding the mode of decomposition of DIC: on exposure to light, DIC undergoes decomposition to dimethylamine and 5-diazoimidazole-4-carboxamide which interacts with nucleic acids in an obscure manner. When light is excluded, however, an alternative pathway of decomposition is followed, with the ultimate formation of 5-aminoimidazole-4-carboxamide and a methyl carbonium ion, which then interacts with cell DNA.
An effect of dexamethasone on adenosine 3',5'-monophosphate content and adenosine 3',5'-monophosphate phosphodiesterase activity of cultured hepatoma cells.
The effect of dexamethasone on adenosine 3',5'-monophosphate (cAMP) phosphodiesterase activity in cultured HTC hepatoma cells was investigated. Homogenates of these cells contain phosphodiesterase activity with two apparent Michaelis constants for cAMP (2-5 mum and 50 mum). At all substrate concentrations tested, phosphodiesterase activity was decreased 25-40% in cells incubated for 36 hr or more with 1 mum dexamethasone. Acid phosphatase activity in the same cells was not decreased. alpha-Methyl testosterone, 1 mum, was without effect on phosphodiesterase activity. Incubation for 10 min with epinephrine plus theophylline increased the cAMP content of the HTC cells 3- to 6-fold. In cells incubated for 72 hr with dexamethasone, the basal concentration of cAMP was slightly increased and the increment produced by epinephrine plus theophylline was markedly increased. We believe that in many cells the so-called permissive effects of steroid hormones on cAMP mediated processes may be due to an effect of these hormones on cAMP phosphodiesterase activity similar to that observed in HTC cells incubated with dexamethasone.