Determinants of response to antimetabolites and their modulation by normal purine and pyrimidine metabolites.

Two areas of investigation are discussed: (a) the identification of critical biochemical parameters that may lead to prediction of response of tumor cells to antimetabolites, such as 1-beta-D-arabinofuranosyl-cytosine (ara-C) and 5-FU, and (b) the potential use of normal purine and pyrimidine metabolites in the selective and specific modulation of critical parameters related to ara-C and 5-FU activity. The results presented indicate a strong correlation between ara-CTP formation and retention in leukemic cells and response of animals with leukemias or patients with acute myelocytic leukemia (AML) treated with ara-C or a protocol containing ara-C. Furthermore, thymidine was found to be an effective modulator of the intracellular pools of dCTP and ara-CTP in rats, bone marrow, small intestine, and colon tumor cells. The mechanism of this effect is unclear, but initial evidence indicates that specific scheduling of the sequential administration of the metabolite and the antimetabolites may be important in determining increased selectivity of antitumor effects. In vivo studies with fluorinated pyrimidines have focused on quantitating 5-fluorodeoxyuridine monophosphate (FdUMP) pools and their retention, and on the incorporation of fluorouridine (FUR) into RNA of sensitive and resistant L1210 cells. The results suggest that the retention of intracellular FdUMP pools above a threshold may be a more critical determinant in selectivity than the initial FdUMP levels achieved in target cells. Thymidine has been demonstrated to alter the pharmacokinetic parameters of 5-FU in man and in mice, but a selective modification of the antitumor activity of 5-FU has not yet been unequivocally demonstrated.