Supra-additive antitumor activity of 5FU with tumor necrosis factor-related apoptosis-inducing ligand on gastric and colon cancers in vitro.
We investigated supra-additive cytotoxic effects of 5-fluorouracil (5FU) on gastric and colon cancer cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in vitro. p53 wild- and mutant-type gastric and colon cancer cell lines were treated by 5FU alone, TRAIL alone, and a combination of 5FU and TRAIL, and cell viability after each treatment was determined by MTT assay. The p53 wild-type cells were more sensitive to 5FU alone or to TRAIL alone than p53 mutant-type cells. The cell growth inhibitory effects of the combined treatment were supra-additive and more significant in proportion to the increasing concentrations of TRAIL as compared with 5FU alone both in p53 wild- and mutant-type cells. Furthermore, TRAIL could cause a decrease in 5FU IC(50) to within the range of clinically relevant doses, particularly in p53 wild-type cells. This is the first demonstration of the supra-additive antitumor activity of 5FU with TRAIL on gastric cancer cells, giving evidence that TRAIL can reduce the requirement for 5FU that ultimately results in minimizing risks for systemic side effects while increasing the antitumor activity of 5FU, suggesting the clinical applicability of this combination for gastric and colon cancers.
Shimoyama
Shouji
S
Department of Gastrointestinal Surgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. shimoyama-dis@h.u-tokyo.ac.jp
Mochizuki
Yoshino
Y
Kusada
Osamu
O
Kaminishi
Michio
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C022616:thiazolyl blue; D005472:Fluorouracil