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Endocrine Control of Cyclic Adenosine 3',5'-Monophosphate Levels in Several Morris Hepatomas¹

McArdle Laboratory for Cancer Research, Medical Center, University of Wisconsin, Madison, Wisconsin 53706 [F. R. B., D. F. S. V. R. P.], and Department of Biochemistry, Howard University, College of Medicine, Washington, D. C. 20001 [H. P. M.]

The effects of glucagon or isoproterenol on cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels were studied in host livers and tumors of Buffalo or A x C rats bearing the following Morris hepatomas: 9618B, 9618A, 66, and 7794B (intact and adrenalectomized); 7794A and 5123C (intact and adrenalectomized); and 7793, 7800, 9098, 9121, and 9108 (intact and adrenalectomized). In most cases, except in the host livers of animals bearing hepatoma 7793, the response of both host liver and tumor to adrenergic stimulation by isoproterenol was equivocal.

The response to glucagon, however, was in contrast to that of isoproterenol. The response to glucagon in 3 hepatomas (9618A, 9618B, and 66) resembled the 50-fold response normally observed in control liver of adult non-tumor-bearing rats. Two tumors of intermediate growth rate gave strikingly different responses to glucagon: cyclic AMP increased only 2-fold in hepatoma 7794B but increased over 100-fold in hepatoma 7794A. Hepatomas 9098, 9121, and 66 gave 2- to 3-fold increases of cyclic AMP levels in response to glucagon; while hepatomas 5123C, 7800, 7793, and 9108 gave little or no response. The responses were charted as a function of the -aminoisobutyrate distribution ratio, which is a measure of the transport capability for certain amino acids, and the relationship was compared with that seen in newborn rats and in young rats of varying ages. Certain hepatomas fell within the range of the normal livers, but a group of hepatomas with high -aminoisobutyrate distribution ratios prior to treatment were shown to have cyclic AMP levels that were remarkably unresponsive to glucagon stimulation.

These results provide new support for the blocked ontogeny hypothesis by showing a resemblance of the highly differentiated hepatomas to more mature liver and a resemblance of another group of hepatomas to fetal or newborn liver, with respect to both naturally occurring and glucagon-stimulated levels of cyclic AMP. The latter group appears to have high -aminoisobutyrate distribution ratios both before and after glucagon treatment.

¹ Financial support was provided in part by Departmental Grant CA-07175 and Training Grant TO1-CA 5002 from the National Cancer Institute.

² Recipient of Postdoctoral Fellowship CA-43800. Present address: Division of Biological and Medical Sciences, Brown University, Providence, R. I. 02912.

³ Recipient of Postdoctoral Fellowship CA-32836. Present address: Department of Cell and Molecular Biology, Medical College of Georgia, Augusta, Ga. 30902.

⁴ To whom requests for reprints should be sent.

⁵ Recipient of Project Grant CA-10729.

Received 2/28/72. Accepted 6/19/72.