Potentiation of Interleukin la Mediated Antitumor Effects by Ketoconazole

In the present studies, the regulatory role of adrenal hormones on the antitumor activity of recombinant human interleukin 1α (IL-1α) was investigated. Ketoconazole, a potent but transient inhibitor of adrenal steroid hormone biosynthesis, inhibited IL-1α induced increases in plasma corticosterone. In s.c. RIF-1 tumors (C3H/HeJ mice) ketoconazole potentiated IL-1α 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-1α combination had no effect on RBC content and little or no effect on tissue perfusion. Ketoconazole potentiation of IL-1α 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-1α at 25 μg/kg alone each produced approximately 50% clonogenic cell kill, a combined treatment (IL-1α 1 h after ketoconazole) resulted in surviving fractions of approximately 1.5%. In vitro, ketoconazole and IL-1α 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-1α 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-1α effect on tumor perfusion, and prevented depletion of tumor high energy phosphate metabolite reserves. Our results are consistent with the hypothesis that IL-1α mediated adrenal hormone responses exert a profound negative feedback on IL-1α 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.