The intracellular content of dihydrofolate reductase: possibilities for control and implications for chemotherapy

Abstract

Intracellular levels of DHFR can be modulated by mechanisms other than gene amplification. We found that MTX itself has an effect and the important features of this mechanism are as follows: (a) Sub-saturating doses of MTX induce intracellular DHFR activity by increasing DHFR synthesis; (b) The time-dependent effect seems quite specific for DHFR and is reversible (7); (c) Elevated DHFR synthesis is accompanied by disproportionate increases in DHFR mRNA; (d) The time scale for maximum induction is appreciably longer than the cell generation time. We suggest that part of the control involved is translational and we postulate that DHFR may regulate its own biosynthesis through feedback mechanisms. It is conceivable that the induction phenomenon could affect the clinical efficacy of MTX-therapy in some instances.