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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.
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
June 1993,
Japanese journal of cancer research : Gann,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
October 1994,
Cancer research,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
January 1994,
Anticancer research,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
October 1991,
Cancer research,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
February 1988,
Cancer research,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
January 1993,
Cancer chemotherapy and pharmacology,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
January 1984,
British medical journal (Clinical research ed.),
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
May 1994,
Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
November 1981,
Cancer research,
P G Braunschweiger, and
N Kumar, and
I Constantinidis, and
J P Wehrle, and
J D Glickson, and
C S Johnson, and
P Furmanski
January 1993,
Cancer research,
