title: Potentiation of interleukin 1 alpha mediated antitumor effects by ketoconazole.
abstract: In the present studies, the regulatory role of adrenal hormones on the antitumor activity of recombinant human interleukin 1 alpha (IL-1 alpha) was investigated. Ketoconazole, a potent but transient inhibitor of adrenal steroid hormone biosynthesis, inhibited IL-1 alpha induced increases in plasma corticosterone. In s.c. RIF-1 tumors (C3H/HeJ mice) ketoconazole potentiated IL-1 alpha induced hemorrhagic necrosis (59Fe labeled RBC uptake) and prolonged intervals of low tumor perfusion (86Rb+ uptake) and attendant depletion of tumor high energy phosphate reserves as determined by in vivo 31P nuclear magnetic resonance spectroscopy. In normal muscle and skin the ketoconazole-IL-1 alpha combination had no effect on RBC content and little or no effect on tissue perfusion. Ketoconazole potentiation of IL-1 alpha induced tumor pathophysiologies was accompanied by time and ketoconazole dose dependent potentiation of RIF-1 tumor clonogenic cell killing. Although ketoconazole at 40 mg/kg and IL-1 alpha at 25 micrograms/kg alone each produced approximately 50% clonogenic cell kill, a combined treatment (IL-1 alpha 1 h after ketoconazole) resulted in surviving fractions of approximately 1.5%. In vitro, ketoconazole and IL-1 alpha induced only additive clonogenic cell kill in primary RIF-1 explant cultures. The effect of elevated plasma corticosterone levels, induced by ketamine-acepromazine anesthesia, on IL-1 alpha responsiveness was also studied in the RIF-1 tumor model. In C3H/HeJ mice, anesthesia increased plasma corticosterone levels within 30 min, abrogated the IL-1 alpha effect on tumor perfusion, and prevented depletion of tumor high energy phosphate metabolite reserves. Our results are consistent with the hypothesis that IL-1 alpha mediated adrenal hormone responses exert a profound negative feedback on IL-1 alpha antitumor activities. Our data also indicate that adrenal steroid hormone biosynthetic pathways could provide a focus for modulation strategies to increase the efficacy of cytokine based therapeutic interventions.
authors.affiliation: Laboratory of Experimental Therapeutics, AMC Cancer Research Center, Denver, Colorado.
authors.forename: P G
authors.initials: PG
authors.lastname: Braunschweiger
authors.forename: N
authors.initials: N
authors.lastname: Kumar
authors.forename: I
authors.initials: I
authors.lastname: Constantinidis
authors.forename: J P
authors.initials: JP
authors.lastname: Wehrle
authors.forename: J D
authors.initials: JD
authors.lastname: Glickson
authors.forename: C S
authors.initials: CS
authors.lastname: Johnson
authors.forename: P
authors.initials: P
authors.lastname: Furmanski
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: D007375:Interleukin-1; D011994:Recombinant Proteins; D007654:Ketoconazole; D003345:Corticosterone