Negative effects of some metabolite analogs in human neoplasms.

The discovery that structurally similar chemi cals may interfere with the utilization of certain essential metabolites has had far-reaching implica tions in the biological sciences. Several recent re views (9, 15) have discussed these types of com pounds and their postulated mechanisms of action. The search among metabolic analogs for chemotherapeutic agents in cancer is predicated upon the hypothesis that neoplastic cells may be affected selectively or to a much greater degree than nor mal cells by the substitution of an antimetabolite in one of the metabolic pathways. This approach is not only conceptually attractive but already has led to the introduction of aminopterin (3, 6, 10) and of 6-mercaptopurine (4) into the clinical man agement of acute leukemia. In this active field the reporting of negative clinical effects as well as positive ones appears to be indicated, in a manner similar to the recent col lation of data on animal trials (12). We are, there fore, recording observations on the use of seven analogs of vitamins, purines, and amino acids in 28 patients with advanced neoplastic disease studied at the Laboratory of Experimental On cology. MATERIALS AND METHODS Twenty-eight patients with advanced neoplastic disease volunteered and were selected for the investigations. All pa tients were deemed to have received maximum benefits from or to have been unsuitable for conventional treatment, such as surgery and radiation. Each patient was observed for at least 1 week for baseline studies, including the necessary laboratory and roentgenographic determinations. To enhance the effects of the antimetabolites, the patients were placed on appropriate diets low in vitamins or in proteins (S, 13). Clinical observations, laboratory studies, and, when prac tical, biopsies were repeated systematically during and after the courses of experimental therapy. Four patients received two courses of single or combined experimental agents. Seven chemical agents, singly or in combination, were used. These were: 8-azaguanine, benzimidazole, aminopterin, isoriboflavin, flavotin, isonicotinic acid hydrazide, and ethionine.1 Aminopterm, flavotin, isoriboflavin, and isonico tinic acid hydrazide were used only in combination with other chemicals. The chemical structures and the metabolites of which the chemicals are analogs are indicated in Chart 1. For intravenous use, 8-azaguanine, benzimidazole, isoriboflavin, and flavotin were finely dispersed in physiological