Enhancement of etoposide and methotrexate sensitivity by indomethacin in vitro.
The possibility of increasing the activity of etoposide (VP-16) by combining this anti-cancer agent with indomethacin (Indo) was investigated by treating murine and human cultured tumor cells with a combination of Indo and VP-16 and quantitating VP-16 cytotoxicity by the [3H]thymidine incorporation assay. Non-toxic concentrations of Indo were found to enhance the sensitivity to VP-16 in cultured Lewis lung carcinoma (LLC), YAC-1, P815, CCRF-CEM and K562 cells which were all relatively sensitive to VP-16. With the LLC, the Indo effect was dose dependent and near maximal at an Indo concentration of 0.5 micrograms/ml. Indo also increased the response of LLC cells to methotrexate, but not to bleomycin. Ibuprofen was less effective than Indo in enhancing VP-16 sensitivity in LLC cells. The enhanced sensitivity of VP-16 by Indo was not reversed by the prostaglandins PGE2 and PGD2, the analogs carbocyclic thromboxane A2 and carba-prostacyclin or conditioned medium removed after 24 h or 48 h of culture from near confluent LLC cell monolayers. This finding suggests that Indo is not augmenting VP-16 cytotoxicity by inhibiting cyclo-oxygenase activity and prostaglandin production. The lipoxygenase inhibitor, eicosatetraynoic acid (ETYA), was also ineffective in reversing the Indo augmentation of VP-16 sensitivity. This finding indicates that Indo is not acting by inhibiting cyclo-oxygenase and converting larger amounts of arachidonic acid to lipoxygenase products, such as leukotrienes, that could then interact with VP-16 to increase its sensitivity. In other studies, Indo was found to significantly increase the steady state accumulation of [3H]-VP-16 in all five cell lines studied. With the LLC cells, this increased steady state was achieved within 15 min after the addition of Indo to these cells and this enhanced VP-16 uptake was not reversed by the addition of prostaglandin E2 or prostaglandin D2. Thus, taken together, these studies indicate that Indo most likely enhances the cytotoxicity of VP-16 by increasing the cellular accumulation of VP-16. This newly identified function of Indo may be of potential clinical significance in the treatment of cancers in man.
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Department of Medicine, Overton Brooks Veterans Affairs Medical Center, Shreveport, Louisiana 71101-4295.
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011453:Prostaglandins / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D047428:Protein Kinase Inhibitors; D001761:Bleomycin; D005047:Etoposide; D007213:Indomethacin; D008727:Methotrexate