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Characteristics of the Cyclic Nucleotide Phosphodiesterases in a Transplantable Pheochromocytoma and Adrenal Medulla of the Rat¹

Department of Pharmacology, Medical College of Pennsylvania, Philadelphia, Pennsylvania 19129

A pheochromocytoma was maintained in rats from the New England Deaconess Hospital by giving the rats s.c. injections of isolated tumor cells. The animals were sacrificed 3 to 4 weeks after transplantation, the tumors were excised, and purified tumor cells were prepared. Cyclic nucleotide phosphodiesterase of the purified tumor cells was characterized and compared with that of the adrenal medulla.

At high concentrations of cyclic adenosine 3':5'-monophosphate (cyclic AMP), the activity of phosphodiesterase from the adrenal medulla was twice that of the pheochromocytoma; but at low substrate concentrations, the cyclic AMP phosphodiesterase activity of the pheochromocytoma was more than 3 times that of the adrenal medulla. By contrast, the rate of hydrolysis of cyclic guanosine 3':5'-monophosphate (cyclic GMP) of the adrenal medulla was approximately 2 times that of the pheochromocytoma at all substrate concentrations studied.

The adrenal medulla and pheochromocytoma displayed biphasic kinetics for cyclic AMP hydrolysis; the apparent Michaelis constants (K_m) for the adrenal medulla (8 and 130 µM) were significantly higher than the K_m's for the pheochromocytoma (0.9 and 18 µM). Kinetic analysis of phosphodiesterase activity in the subcellular components demonstrated that in the pheochromocytoma all fractions contained the high-affinity form of phosphodiesterase. However, in the adrenal medulla only the nuclear fraction contained a high-affinity form of phosphodiesterase.

Theophylline, papaverine, cyclic GMP, trifluoperazine, and dipyridamole were relatively ineffective in inhibiting the cyclic AMP phosphodiesterase from either the adrenal medulla or pheochromocytoma.

Our findings that the pheochromocytoma has a greater activity of a high-affinity cyclic AMP phosphodiesterase but a lesser activity of cyclic GMP phosphodiesterase when compared with that of the normal adrenal medulla suggest that pheochromocytoma cells may have a relatively low ratio of cyclic AMP to cyclic GMP. This is consistent with the proposition that low intracellular concentrations of cyclic AMP or a low ratio of cyclic AMP to cyclic GMP may be associated with neoplastic activity.

¹ Supported by Grant CA15883 awarded by the National Cancer Institute, Department of Health, Education and Welfare.

Received 4/27/77. Accepted 1/ 4/78.