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Regulation of Adenyl Cyclase in Hepatomas of Different Growth Rates¹

Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [D. O. A., J. M., G. W.], and Department of Biochemistry, Howard University School of Medicine, Washington, D. C. 20001 [H. P. M.]

Adenyl cyclase activity was measured without addition and in the presence of sodium fluoride or glucagon in six lines of hepatomas representing different growth rates. The values were compared with those in control, normal rat livers from animals of the same strain, sex, age, and weight as the tumor-bearing rats. The enzyme activity in 24-hr regenerating liver was compared with that in the liver of sham-operated rats.

Hepatic adenyl cyclase activity was in the same range in normal rats of Buffalo, ACI/N, and Holtzman strain and in sham-operated and partially hepatectomized rats. The activities of all hepatomas were in the range of those in normal or regenerating liver.

Addition of sodium fluoride to the enzyme assay system caused an 8- to 10-fold increase in adenyl cyclase activity in all examined normal, regenerating, and neoplastic livers.

Glucagon caused an increase to 236 to 343% in normal and regenerating livers. Glucagon stimulation resulted in a similar significant increase in the slowly growing hepatomas (9618-B, 7787) and in one line of the medium-growth-rate tumors (5123-t.c.). However, there was no significant glucagon response in the more rapidly growing hepatoma, 7288-C, nor in the very rapidly growing hepatomas (3924-A, 9618-A₂). Thus, the responsiveness to glucagon stimulation declined with the increase in hepatoma growth rate.

In view of evidence for the presence of two types of cyclase systems in the liver, the present results are compatible with the suggestion that the glucagon-responsive adenyl cyclase, which occurs chiefly in the liver, is the one that has lost its responsiveness to stimulation by this hormone in the rapidly growing hepatomas.

¹ This investigation was supported by American Cancer Society Institutional Grant IN46K (D. O. A.); USPHS Grant CA-10729 (H. P. M.); USPHS Grant CA-05034, the American Cancer Society, and the Damon Runyon Memorial Fund, Inc. (G. W.).

Received 9/ 4/70. Accepted 1/ 4/71.

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