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.
Action of bredinin on mammalian cells.
Bredinin, a new nucleoside antibiotic, inhibited multiplication of several mammalian cell lines in culture and had a cytotoxic effect on L5178Y cells. Growth inhibition by bredinin was prevented by guanosine 5'-monophosphate (GMP), guanosine, or guanine but not by other purine or pyrimidine nucleotides, nucleosides, or bases. Inhibition by bredinin at a low GMP; but at higher concentrations of bredinin the inhibition was not reversed even when the concentration of GMP was raised. Addition of GMP after cellular damage had occurred produced no effect on the damaged cells but it prvented further damage. Bredinin caused marked chromosomal aberrations such as breakages, translocations, and fragmentation in L5178Y cells.
Effect of radiation-sensitizing agents in radiation therapy of mouse mammary carcinoma.
IUdR, injected intraperitoneally, did not cause cell death for tumor cells proliferating as small colonies in subcutaneous tissues. Only a small amount of TdR of total DNA was replaced. A small fraction of the cells seemed to be in active cell proliferation, and they efficiently utilized the injected IUdR. At completion of the injections, nearly all cells in the aerobic and hypoxic compartments which are viable have been through at least one S period in the preceding forty-eight hours.