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Increased Cyclic Nucleotide Phosphodiesterase Activity Associated with Proliferation and Cancer in Human and Murine Lymphoid Cells¹

Department of Pharmacology, The University of Texas Medical School at Houston and The University of Texas Systems Cancer Center, M. D. Anderson Hospital, Houston, Texas 77030

Guanosine cyclic 3':5'-monophosphate phosphodiesterase activity of murine leukemic cells (L1210) was 400 times that of human peripheral blood lymphocytes and 15 times that of murine splenic lymphocytes. Adenosine cyclic 3':5'-monophosphate (cyclic AMP) phosphodiesterase activity of L1210 cells was 320 times that of human peripheral blood lymphocytes and 24 times that of normal murine lymphocytes. The total cyclic AMP and guanosine cyclic 3':5'-monophosphate phosphodiesterase activities of rapidly growing cultured human lymphoid cells (normal and leukemic lymphoblastoid cell lines) were also markedly elevated when compared to quiescent peripheral blood lymphocytes. Human peripheral blood lymphocytes stimulated by phytohemagglutinin showed a 10-fold increase in total enzyme activity.

Leukemic and normal murine cells contain a low-affinity cyclic AMP phosphodiesterase as normally observed in most mammalian tissues. In contrast, kinetic analyses of cyclic AMP phosphodiesterase activities of human B and T lymphoblastoid cells were similar to those of peripheral blood lymphocytes in that no evidence of a low-affinity enzyme was found. All the lymphoid cells tested showed a 3 to 4 S enzyme form by linear sucrose gradient fractionation. Proliferating and quiescent human cells also contain a higher-molecular-weight cyclic AMP-specific form (5.9 S), while the murine cells contain a 7.0 S higher-molecular-weight form. Both the 5.9 and 7.0 S forms show anomalous kinetic behavior. These results are discussed with respect to the biochemical nature of cyclic nucleotide phosphodiesterases and the role of this enzyme system in the proliferation of lymphoid cells.

¹ Supported by USPHS Grants GM-21361, CA-05831, CA-14984, and CA-14980-03 and the Pulaski County Cancer Society.

² Fellow of The Rosalie B. Hite Foundation.

Received 3/10/77. Accepted 7/29/77.