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Comparison of Cyclic Adenosine 3':5'-Monophosphate and Cyclic Guanosine 3':5'-Monophosphate Levels, Cyclases, and Phosphodiesterases in Morris Hepatomas and Liver¹

Department of Pharmacology, University of Texas Medical School at Houston [R. A. H., W. J. T., S. J. S., B. C-M., G. A. R.], and Department of Developmental Therapeutics, M. D. Anderson Hospital and Tumor Institute, Texas Medical Center, Houston, Texas 77030 [R. A. H.]; and Department of Biochemistry, College of Medicine, Howard University, Washington, D. C. 20059 [H. P. M.]

As a test of the hypothesis that cell proliferation is regulated by opposing effects of cyclic adenosine 3':5'-monophosphate (cAMP) and cyclic guanosine 3':5'-monophosphate (cGMP), the levels of these cyclic nucleotides were investigated in a rapidly growing hepatoma (7288ctc), two intermediate-growth-rate tumors [5123tc (h) and 5123C], one slow-growing hepatoma (7794A), host liver, and normal liver. Changes in cyclic nucleotide levels were also compared to alterations in activities of the soluble and particulate cyclases and phosphodiesterases in these tissues.

In hepatoma 7288ctc the cAMP content was slightly lower than that in normal liver (12%), whereas the cGMP levels were more than 4-fold higher. The cAMP levels of 5123tc (h) and 5123C were 20 to 27% lower, whereas the cGMP levels were 25 to 33% higher than those of normal liver. For 7794A the cAMP content was 42% higher than that in normal liver, whereas the cGMP levels were 75% higher. In host livers the cAMP levels were usually higher than those in normal liver (22 to 47%) in animals bearing the rapidly growing and intermediate-growth-rate hepatomas; host liver cGMP levels also tended to be 17 to 33% higher than those of normal liver. Although the cGMP/cAMP ratios are generally higher in hepatomas than they are in normal liver, there is no direct correlation between tumor growth rate and cyclic nucleotide content or the corresponding cGMP/cAMP ratios.

Changes in enzyme activities common to all four hepatomas included reduced activities of the total particulate cAMP phosphodiesterases as well as depressed activities of soluble guanylyl cyclase and particulate cGMP phosphodiesterase. The responsiveness of adenylyl cyclase to glucagon was impaired to a greater degree in the rapid- and intermediate-growth-rate tumors than it was in the slow-growing one; this observation confirms previous findings of other workers on different hepatomas. The total activities of the apparent high-affinity (low-K_m) cAMP phosphodiesterase were substantially lower than those of normal liver in 7288ctc, 5123C, and 7794A but were similar to those of liver in 5123tc (h); some of the particulate fractions of the latter tumor actually had specific activities that exceeded those of normal liver. It is concluded that the cGMP/cAMP ratios observed in this study coincide more closely with specific changes in activities of the cyclases and/or phosphodiesterases than with differences in hepatoma growth rate.

¹ Supported by the National Cancer Institute of Canada and by USPHS Grants GM-21361, HL-16552, and CA-10729. A preliminary report of this study was presented at the 67th Annual Meeting of the American Society of Biological Chemists, San Francisco, Calif., June 10, 1976 (Federation Proc., 35: 1714, 1976).

² To whom requests for reprints should be addressed. Present address: Department of Pharmacology, Faculty of Medicine, Health Sciences Building, University of Saskatchewan, Sakatoon, Saskatchewan, Canada S7N 0W0.

Received 9/14/76. Accepted 7/ 1/77.