Effect of chlorambucil and indomethacin on growth and prostaglandin levels in sensitive and resistant Walker carcinoma.
An analysis of the effect of combinations of chlorambucil and indomethacin, or chlorambucil and prostaglandin E2 (PGE2) on the growth of alkylating agent sensitive and resistant Walker carcinoma in vitro has been made by the isobologram approach. Indomethacin alone acts as a growth inhibitor of the Walker carcinoma. High concentrations of indomethacin (5 microgram/ml) act to inhibit the growth of the resistant line sub-additively with chlorambucil, whereas low concentrations act additively. For the sensitive line indomethacin acts either additively or supra-additively with chlorambucil at all concentrations employed. Both indomethacin and low concentrations of chlorambucil alone inhibit PGE2 secretion into the culture medium of both cell lines and an enhanced inhibition is seen with the combination. PGE2 itself acts as a growth inhibitor of both cell lines, although it causes greater growth inhibition of chlorambucil resistant Walker carcinoma (LD50 1.8 microgram/ml) than of the sensitive line. This correlates with a greater PGE2 secretion capacity by the resistant cell line (40 pg PGE2/ml medium/10(5) cells for the resistant tumour and 17 pg PGE2/ml medium/10(5) cells for the sensitive tumour). Combinations of PGE2 with chlorambucil inhibit growth either additively or sub-additively. It seems unlikely that inhibition of PGE2 secretion is responsible for the interactive effects of chlorambucil and indomethacin, since growth inhibition produced by the combination is not reversed by PGE2 at any of the concentrations employed. Possible mechanisms of the interactive effects are discussed.
D000818:Animals; D002279:Carcinoma 256, Walker / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D002699:Chlorambucil / Q000494:pharmacology*; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D007213:Indomethacin / Q000494:pharmacology*; D051379:Mice; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000494:pharmacology*
D011453:Prostaglandins; D011458:Prostaglandins E; D002699:Chlorambucil; D015232:Dinoprostone; D007213:Indomethacin