Pretreatment of colon carcinoma cells with Tomudex enhances 5-fluorouracil cytotoxicity.
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.
Longo
G S
GS
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Izzo
J
J
Chang
Y M
YM
Tong
W P
WP
Zielinski
Z
Z
Gorlick
R
R
Chou
T C
TC
Bertino
J R
JR
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016923:Cell Death / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D009711:Nucleotides / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D012334:RNA, Neoplasm / Q000378:metabolism; D013876:Thiophenes / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D009711:Nucleotides; D011799:Quinazolines; D012334:RNA, Neoplasm; D013876:Thiophenes; D010754:Phosphoribosyl Pyrophosphate; D013940:Thymidylate Synthase; C068874:raltitrexed; D005472:Fluorouracil