Pretreatment of colon carcinoma cells with Tomudex enhances 5-fluorouracil cytotoxicity Journal Article
| Authors: | Longo, G. S. A.; Izzo, J.; Chang, Y. M.; Tong, W. P.; Zielinski, Z.; Gorlick, R.; Chou, T. C.; Bertino, J. R. |
| Article Title: | Pretreatment of colon carcinoma cells with Tomudex enhances 5-fluorouracil cytotoxicity |
| Abstract: | The cytotoxic effect of sequence and dose of Tomudex (TX) and 5- fluorouracil (FUra) on an HCT-8 colon carcinoma cell line using a clonogenic assay was evaluated. Synergistic cell kill was obtained with 24 h of exposure to TX followed by 4 h of exposure to FUra. Marginal synergy was obtained with the same sequence but with a 5-day exposure to FUra. The reverse sequence, FUra (either 4 h or 5 days), followed by TX (24 h), resulted in less-than- additive cell kill. The synergistic effect was not due to augmented inhibition of thymidylate synthase, as determined by the measurement of thymidylate synthase activity by tritium release from [5-3H]2'-deoxyuridine. Surprisingly, an increase in intracellular levels of phosphoribosylpyrophosphate was observed after 24 h of exposure to TX, suggesting the possibility of an indirect effect of TX and/or its polyglutamates on purine biosynthesis. Moreover, we observed an increased formation of FUra nucleotides in the cells preexposed to TX, likely due to the increased intracellular levels of phosphoribosylpyrophosphate, that as a consequence led to an enhanced incorporation of FUra into RNA and increased cell killing. |
| Keywords: | cancer survival; human cell; fluorouracil; advanced cancer; adenocarcinoma; cell death; enzyme inhibition; antineoplastic combined chemotherapy protocols; drug administration schedule; colonic neoplasms; continuous infusion; cytotoxicity; dose-response relationship, drug; tumor cells, cultured; drug synergism; colon carcinoma; thymidylate synthase; quinazolines; clonogenic assay; rna, neoplasm; carcinoma cell; rna metabolism; cell killing; nucleotides; thiophenes; raltitrexed; humans; human; priority journal; article; purine synthesis; phosphoribosyl pyrophosphate |
| Journal Title: | Clinical Cancer Research |
| Volume: | 4 |
| Issue: | 2 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 1998-02-01 |
| Start Page: | 469 |
| End Page: | 473 |
| Language: | English |
| PUBMED: | 9516938 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 12 December 2016 -- Source: Scopus |
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