Indomethacin increases the cytotoxicity of cis-platinum and 5-fluorouracil in the human uterine cervical cancer cell lines SKG-2 and HKUS by increasing the intracellular uptake of the agents.
BACKGROUND
Various approaches have been made to increase the cytotoxicity of cis-platinum (CDDP) and 5-fluorouracil (5FUra), and to reduce their adverse effects. We used two human cancer cell lines of the uterine cervix (SKG-2 and HKUS) and selected indomethacin as a modifying agent to assess its effect on the cytotoxicity of CDDP and 5FUra.


METHODS
The effect of indomethacin on the cytotoxicity of CDDP and 5FUra in these tumor cells was evaluated by in-vitro Alamar blue assay, and intracellular uptake of free-CDDP and 5FUra was measured to find out how indomethacin modified the cytotoxicity of CDDP and 5FUra.


RESULTS
Indomethacin showed no cytotoxic effect on these tumor cells, but significantly (P < 0.005-0.001) increased the cytotoxicity of both CDDP and 5FUra, compared with single treatment by each agent. The intracellular uptake of both free-CDDP and 5FUra was measured in culture media containing the agents alone (single treatment) or the agents with indomethacin (0.001, 0.01, and 0.1 microgram/ml; combined treatment). The intracellular contents of both free-CDDP (SKG-2, HKUS; P < 0.001) and 5FUra (SKG-2; P < 0.005, HKUS; P < 0.02) were significantly higher in the combined treatment than in the single treatment.


CONCLUSIONS
This study shows that indomethacin increased the cytotoxicity of both CDDP and 5FUra by increasing the intracellular incorporation of free-CDDP and 5FUra, and suggests the effectiveness of indomethacin in reducing the dosage of CDDP and 5FUra or increasing CDDP and 5FUra cytotoxicity when these agents are given without reducing the dose.
Ogino
M
M
Department of Obstetrics and Gynecology, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. mogino@cb3.so-net.ne.jp
Minoura
S
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil; D007213:Indomethacin