The effects of A-methopterin on the in vitro incorporation of P32O4 into normal and leukemic mouse tissues.

Certain folie acid antagonists have been shown by Farber (8) and by others (3, 5, 19, 29) to pro duce temporary remissions of acute leukemia in children. A therapeutic action of these agents, re sulting in a prolongation of survival time in mice bearing transplantable leukemias, has been de scribed by Burchenal et al. (2), by Law et cd. (17), and by Kirschbaum (12). Folie acid antagonistresistant sublines of transplantable mouse leu kemias have been developed (4, 13-16, 21) the resistance residing in the leukemic cells rather than in the hosts (see review by Kirschbaum [12]). It seems likely that the inhibitory action of the folie acid antagonists involves an interference with the metabolic function of folie acid and its derivatives, and, as a consequence of this interference, abnor malities in the metabolism of one-carbon units (for example, formate) and of nucleic acids may arise (9-11, 18, 20, 23-27, 30). The biochemical basis for the development of resistance to folie acid antagonists by leukemias is not understood. The resistance (or dépendance)in leukemic cells is stable, irreversible, and heritable. It has been shown that this change is a mutation, the drug acting to select out surviving leukemic cells (15). It is of considerable importance to elucidate the mechanisms by which folie acid antagonists (FAA) inhibit the growth of leukemic tissues and to ascertain the biochemical basis for the resist ance which develops to these agents. Toward this end an investigation has been undertaken on the in vitro incorporation of P32O.i>glucose-C14, and formate-C14 into the proteins and pentosenucleic acid of normal and leukemic tissues in the presence