Studies on 1-beta-D-arabinofuranosyl cytosine-resistant mutants of Chinese hamster fibroblasts: III. Joint resistance to arabinofuranosyl cytosine and to excess thymidine--a semidominant manifestation of deoxycytidine triphosphate pool expansion.

Variants isolated from mutagenized Chinese hamster fibroblasts by a single cycle of exposure to ara-C distributed into two classes: (1) deoxycytidine (dC) kinase deficient clones with a high level of resistance, this phenotype was recessive in hybrids; and (2) clones exhibiting joint resistance to thymidine (dT) and to "low" ara-C concentration, this phenotype was accounted for by an increased dCTP pool. The incorporation of exogenous dC into macromolecules was markedly altered in these variants. In hybrids, the phenotype of joint resistance to dT and ara-C was semidominant. Through a second selection step, variants cumulating recessive high resistance to ara-C and semidominant dT resistance were recovered. The identification of these two classes of ara-C-resistant variants suggests an interpretation of the known phenotypes of ara-C resistance as manifestations of chromosomal gene mutations. Dominant resistance mutations might contribute to the survival of cancer cells during prolonged ara-C chemotherapy.