Study for The Development of Anti-cancer Drug Based on A New Mechanism of Actions

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Retinoic acid (RA) is used clinically in the treatment of proliferative dermatological diseases and leukemia, and in the prevention of some tumors. However, a high percentage of acute promyelocytic leukemia patients in completer remission induced by RA alone relapsed within a few months. Most relapsed patients are resistant to further treatment with RA. This let us to develop new drugs by the elucidation of retinoylation (acylation by RA of protein), a new non-genomic mechanism by w3hich RA may act on cells. We found that recently identified new steroid and polyene enhanced RA action, the induction of cell differentiation, and increased the extent of retinoylation. In addition, they as a sole agent, exhibited anti-cancer activities. One metabolic pathway for retinoylation is the formation of a retinoyl-CoA intermediate and subsequent transfer and covalent binding of the retinoyl moiety to protein. We established in vitro assays for retinoylation, retinoyl-CoA synthetase and retinoyl-CoA transferase by using rat tissues. Enzyme activities depended on time, and the concentration of substrate and enzyme in a saturable manner. The omission of any of ATP, CoA and MhClィイD22ィエD2 resulted in a marked reduction of retinoyl-CoA formation. The level of retinoylation was proportional to the amount of retinoyl-CoA formed in crude extracts of rat liver, testis, and kidney, and there existed the positive correlation between them. These results indicate that the enzyme activity which is responsible for the ATP-dependent retinoyl-CoA formation from RA exists in rat liver. The established sensitive method of both exzyme activities seems to be useful for the clarification of physiological role of the retinoylaton. Studies are presently underway to determine the toxicity and the effectiveness of combination of RA and polyenes on tumors growing in animals.