Leucovorin enhances cytotoxicity of trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in CCRF-CEM cells Journal Article
| Authors: | Romanini, A.; Li, W. W.; Colofiore, J. R.; Bertino, J. R. |
| Article Title: | Leucovorin enhances cytotoxicity of trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in CCRF-CEM cells |
| Abstract: | Background: Increased response rates in studies of patients with colon cancer have indicated that the cytotoxic effects of fluorouracil (5-FU) are potentiated by leucovorin (LV) and by methotrexate (MTX). However, preliminary studies using a sequential combination of MTX, LV, and 5-FU showed no additional potentiation. Purpose: We hypothesized that the lack of additional cell kill with this combination could be due to competition of LV with MTX for cellular uptake and reduced folate polygluta-mylation. We have tested this possibility by comparing the cytotoxicity of drug combinations containing MTX with that of drug combinations containing trimetrexate (TMTX), an anti-folate that does not compete with LV for uptake or polyglutamylation. Methods: Human lymphocytic leukemia CCRF-CEM cells were exposed to MTX or TMTX for 24 hours and to 5-FU during the last 4 hours of antifo-late exposure. LV was administered 30 minutes before 5-FU. Results: After 20 hours of exposure to TMTX or MTX, intracellular levels of phosphoribosyl pyrophosphate were elevated to a similar degree, and these levels did not decrease after a 30-minute exposure to LV. No additional cell kill was observed when LV was added to the MTX/5-FU combination, but cytotoxicity was enhanced when LV was added to the TMTX/5-FU combination. Conclusions: This study supports the hypothesis that the lack of additional cell kill when high-dose LV is added to the MTX/5-FU combination may be due to competition of MTX with LV for cellular uptake and/or competition of MTX or its polygluta-mates with polyglutamylation of reduced folates. Inasmuch as TMTX does not compete with LV and reduced folates for uptake and polyglutamylation, the synergy obtained with the combination of TMTX plus 5-FU and high-dose LV further supports this hypothesis. [J Natl Cancer Inst 84:1033-1038, 1992] © 1992 Oxford University Press. |
| Keywords: | cancer chemotherapy; human cell; fluorouracil; drug potentiation; methotrexate; cell survival; antineoplastic combined chemotherapy protocols; cytotoxicity; dose-response relationship, drug; tumor cells, cultured; drug synergism; drug mechanism; folinic acid; leukemia cell; lymphatic leukemia; leucovorin; concentration response; trimetrexate; drug mixture; leukemia, lymphocytic; human; priority journal; article; phosphoribosyl pyrophosphate |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 84 |
| Issue: | 13 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 1992-07-01 |
| Start Page: | 1033 |
| End Page: | 1038 |
| Language: | English |
| DOI: | 10.1093/jnci/84.13.1033 |
| PUBMED: | 1376779 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
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