REVERSAL OF TUMOR-ASSOCIATED HYPERGLUCAGONEMIA AS TREATMENT FOR CANCER CACHEXIA

Background. The tumor-bearing state is associated with increased circu lating glucagon levels that may play an etiologic rob in cancer cachex ia. The secretion of glucagon can be inhibited with long-term somatost atin analogs, and, in combination with insulin, should maximally rever se the low insulin/glucagon ratio seen in cancer cachexia. The goal of this study is to examine the effect of somatostatin (octreotide) and insulin in a model of cancer cachexia and to determine whether inhibit ion of glucagon secretion will reverse some of the abnormalities in ca rbohydrate metabolism to selectively benefit host versus tumor metabol ism. Methods. Sixty-seven female Lewis rats were subcutaneously inocul ated with 1 x 10(6) metastasizing mammary adenocarcinoma tumor cells. On day 30 the animals were randomized into four groups to receive (1) tumor-bearing control (saline injections); (2) octreotide, 150 mu g/kg intraperitoneally twice a day; (3) neutral protamine Hagedorn insulin , 5 units/kg subcutaneously twice a day; or (4) both insulin and octre otide injections. A fifth group of non-tumor-bearing controls was incl uded. The animals received treatment for 5 days and were then killed. Results. The tumor-bearing state was found to be associated with an in crease in glucagon levels and a significant decrease in the insulin/gl ucagon ratio. The combination of somatostatin + insulin resulted in a 23-fold increase in the insulin/glucagon ratio without causing signifi cant host morbidity from hypoglycemia. This increased insulin/glucagon ratio was associated with increased carcass weight, increased muscle weight, increased muscle protein increased liver cellular protein, inc reased liver microsomal P-450 content, and decreased tumor protein con tent compared with the tumor-bearing controls. These results were not seen with insulin or somatostatin alone. Hepatic lactate dehydrogenase , glucose-6-phosphatase, and fructose-1, 6-diphosphatase activities we re increased as a result of combination hormone treatment. Conclusions . Combination hormone treatment with somatostatin and insulin results in a marked increase in the insulin/glucagon ratio and a selective nut ritional benefit to the host. The inhibition of tumor-associated hyper glucagonemia should be considered in the treatment of cancer cachexia.