Biochemical Rationale for Selectivity in the Modulation of Methotrexate Activity During Leucovorin Rescue or Early Nucleoside Protection

Abstract

The first successful modulation of the selectivity of an antineoplastic agent was demonstrated by Goldin and his coworkers in the 1950 ’s with the leucovorin rescue phenomenon as an approach to the enhancement of the chemotherapeutic efficacy of 4-amino antifolates in murine tumor systems (1). This modality was introduced in the clinics in the following decade and remains an important component of many chemotherapeutic regimens (2, 3). Despite its widespread use, neither the mechanism by which leucovorin circumvents the biochemical and cytotoxic effects of methotrexate nor the selectivity of this phenomenon have been clearly elucidated; this area remains a focus of investigative activities in this and other laboratories. There have been other approaches utilized in an attempt to modulate antifolate activity, for instance, the application of thymidine in regimens with methotrexate (4, 5, 6). This nucleoside circumvents the need for tetrahydrofolate cofactors by providing the end-product of tetrahydrofolate-dependent thymidylate synthesis. However, no clear biochemical rationale has been defined that could provide a basis for an inherent selectivity in the use of thymidine with methotrexate as an antineoplastic regimen.