Biochemical modulation of fluorouracil with leucovorin and interferon: preclinical and clinical investigations.
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-alpha-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.
Grem
J L
JL
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Chu
E
E
Boarman
D
D
Balis
F M
FM
Murphy
R F
RF
McAtee
N
N
Allegra
C J
CJ
D003110:Colonic Neoplasms / Q000378:metabolism* / Q000628:therapy; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000628:therapy*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D002955:Leucovorin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D009382:Neoplasms, Unknown Primary / Q000378:metabolism / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy; D011994:Recombinant Proteins; D013274:Stomach Neoplasms / Q000378:metabolism / Q000628:therapy*; D013763:Tetrahydrofolates / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D007371:Interferon-gamma; D002955:Leucovorin; D005472:Fluorouracil