The iv administration of low doses of recombinant human Tumor Necrosis Factor (rhTNF) to awake unrestrained rats increases plasma levels of glucagon, corticosterone, ACTH, norepinephrine and dihydroxyphenylglycol. Incubation of human adrenocortical cells with TNF causes cortisol secretion similar to incubation with ACTH. Local application of cachectin/TNF is detrimental to wound healing. Insulin therapy reverses the toxic effects of TNF including improvement of food intake, body weight and the cellular changes associated with TNF treatment. Tolerance to the toxic effects of rhTNF can be induced in animals by repetitive exposure to doses of rhTNF. In animals undergoing TNF anti-tumor therapy tolerance to the anti-tumor effects of rhTNF also develops limiting the treatment efficacy of TNF. Similarly, TB rats made tolerance to rhTNF by repetitive twice daily ip doses for 7-14 days appear to tolerate the cachectic effects of tumor and eat more, maintain body weight and survive longer than control TB animals. Tolerance is only induced by intermittent bolus doses of rhTNF. Continuous iv doses results in maintenance of severe anorexia, body weight loss and death, while bolus iv applications of the same dose does not. Tumors exist in an acidic environment with high concentrations of lactic acid as a result of anaerobic glycolysis. Macrophages exposed to a similar environment induce the gene for TNF and secrete excessive amounts of TNF as do macrophages exposed to photodynamic therapy. An antibody to interferon-gamma reverses the clinical parameters of cachexia in TB rats and allows cachectic TB rats to live longer than control TB rats. Adrenal tumors are rare causes of Cushing's syndrome. Benign tumors are curable with resection but recovery of the HPA axis and cessation of replacement doses of hydrocortisone requires nearly 2 years. Malignant adrenal tumors generally recur locally or systemically. There is no curative therapy for recurrent adrenal cancer, but surgical resection of recurrent disease is associated with longer survival from the time of recurrence.
