ENHANCEMENT OF CHEMOTHERAPEUTIC DRUG TOXICITY TO HUMAN TUMOR-CELLS IN-VITRO BY A SUBSET OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS)

The effect on cytotoxicity of combining a range of clinically importan t non-steroidal anti-inflammatory drugs (NSAIDs) with a variety of che motherapeutic drugs was examined in the human lung cancer cell Lines D LKP, A549, COR L23P and COR L23R and in a human leukaemia line HL60/AD R. A specific group of NSAIDs (indomethacin, sulindac, tolmetin, aceme tacin, zomepirac and mefenamic acid) all at non-toxic levels, signific antly increased the cytotoxicity of the anthracyclines (doxorubicin, d aunorubicin and epirubicin), as well as teniposide, VP-16 and vincrist ine, but not the other vinca alkaloids vinblastine and vinorelbine. A substantial number of other anticancer drugs, including methotrexate, 5-fluorouracil, cytarabine, hydroxyurea, chlorambucil, cyclophosphamid e, cisplatin, carboplatin, mitoxantrone, actinomycin D, bleomycin, pac litaxel and camptothecin, were also tested, but displayed no synergy i n combination with the NSAIDs. The synergistic effect was concentratio n dependent. The effect appears to be independent of the cyclo-oxygena se inhibitory ability of the NSAIDs, as (i) the synergistic combinatio n could not be reversed by the addition of prostaglandins D-2 or E-2; (ii) sulindac sulphone, a metabolite of sulindac that does not inhibit the cyclooxygenase enzyme, was positive in the combination assay: and (iii) many NSAIDs known to be cyclo-oxygenase inhibitors, e.g. meclof enamic acid, diclofenac, naproxen, fenoprofen, phenylbutazone, flufena mic acid, flurbiprofen, ibuprofen and ketoprofen, were inactive in the combination assay. The enhancement of cytotoxicity was observed in a range of drug sensitive tumour cell lines, but did not occur in P-170- overexpressing multidrug resistant cell lines. However, in the HL60/AD R and COR L23R cell lines, in which multidrug resistance is due to ove rexpression of the multidrug resistance-associated protein MRP, a sign ificant increase in cytotoxicity was observed in the presence of the a ctive NSAIDs. Subsequent Western blot analysis of the drug sensitive p arental cell lines, DLKP and A549, revealed that they also expressed M RP and reverse-transcription-polymerase chain reaction studies demonst rated that mRNA for MRP was present in both cell Lines. It was found t hat the positive NSAIDs were among the more potent inhibitors of [H-3] -LTC4 transport into inside-out plasma membrane vesicles prepared from MRP-expressing cells, of doxorubicin efflux from preloaded cells and of glutathione-S-transferase activity. The NSAIDs did not enhance cell ular sensitivity to radiation. The combination of specific NSAIDs with anticancer drugs reported here may have potential clinical applicatio ns, especially in the circumvention of MRP-mediated multidrug resistan ce. (C) 1998 Elsevier Science Ltd. All rights reserved.