Biochemical modulation of fluorouracil with leucovorin and interferon: Preclinical and clinical investigations

Jean L. Grem, Edward Chu, Donna Boarman, Frank M. Balis, Robert F. Murphy, Nanette McAtee, Carmen J. Allegra

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Leucovorin and interferon are capable of modulating the cytotoxicity of fluorouracil (5-FU). Preclinical studies demonstrate that d,l-leucovorin is rapidly metabolized in human breast and colon cells into the various one-carbon substituted folate pools and to the polyglutamated state. While increases in intracellular folate pools are proportional to the exposure concentration of leucovorin, relatively large increases in leucovorin concentrations (50-to 100-fold) are required to produce small intracellular changes (twofold). Polyglutamation is favored by prolonged exposures to leucovorin. Polyglutamate forms have a prolonged intracellular retention and a higher affinity for the target enzyme, thymidylate synthase. Ratios of up to 20:1 inactive to active leucovorin stereo-isomers had essentially no effect on the intracellular metabolism of the active isomer. Interferon gamma interacts with 5-FU in H630 colon cancer cells at the level of thymidylate synthase and enhances cytotoxicity of 5-FU by eliminating the 5-FU-induced acute overexpression of the target enzyme. No alterations in the intracellular metabolism or nucleic acid incorporation of 5-FU could be demonstrated with the addition of interferon gamma. A clinical trial combining interferon-alfa-2a (IFN-α-2a) (subcutaneous days 1 to 7) with 5-FU and leucovorin (given IV days 2 to 6) demonstrated that these agents could be combined with acceptable toxicity. While the addition of interferon did not allow dose escalation of 5-FU, it resulted in a significant increase in drug exposure (1.5-fold) compared with matched cycles of 5-FU plus leucovorin without interferon. The overall response rate in this pilot study of 13 untreated patients with gastrointestinal adenocarcinoma was 46%, including two complete responses. There were no responses in eight patients who had previously failed therapy with 5-FU. This is a US government work. There are no restrictions on its use.

Original languageEnglish (US)
Pages (from-to)36-44
Number of pages9
JournalSeminars in Oncology
Volume19
Issue number2 SUPPL. 3
StatePublished - Apr 1992

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Grem, J. L., Chu, E., Boarman, D., Balis, F. M., Murphy, R. F., McAtee, N., & Allegra, C. J. (1992). Biochemical modulation of fluorouracil with leucovorin and interferon: Preclinical and clinical investigations. Seminars in Oncology, 19(2 SUPPL. 3), 36-44.