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Analyses of Cyclic Nucleotide Phosphodiesterases in Lymphocytes from Normal and Aged Leukemic Mice¹

Department of Pharmacology, The Medical College of Pennsylvania, Philadelphia, Pennsylvania 19129 [B. W.], and Section of Immunology and Cell Biology, Baltimore Cancer Research Center, NIH, Baltimore, Maryland 21211 [R. A. W.]

The activity of cyclic 3':5'-nucleotide phosphodiesterase was measured in thymocytes and splenic lymphocytes of AKR mice of various ages. Concurrently, the cell distribution profiles of these cell populations were studied by laser cytometric analysis. The results indicate that lymphocyte and thymocyte populations from young, control animals are relatively homogeneous with respect to cell size, whereas cell populations from old, leukemic mice showed increases in the percentage of larger, blast-like cells. These latter cell populations also showed increases in cyclic nucleotide phosphodiesterase activity when compared with that of young animals. Old, nontumor-bearing mice had lower levels of enzyme activity than did their leukemic counterparts and showed only modest increases in the percentage of blast-like cells. Correlation analyses revealed that increases in enzyme activity correlated with increases in the percentage of large cells but not with increases in thymus weight. These data suggest that increases in phosphodiesterase activity are associated with the appearance of leukemic cells and not with a putative preleukemic state.

Preparative polyacrylamide gel electrophoresis revealed multiple forms of both cyclic adenosine and cyclic guanosine 3':5'-phosphodiesterases. The pattern of the phosphodiesterases showed distinct differences between normal and leukemic thymocytes. The major differences were a reduction in the more slowly migrating forms and a large increase in the activity of one form of the enzyme in the leukemic cells. This suggests that selective inhibition of this form of phosphodiesterase might be effective therapy for certain types of leukemias.

¹ This investigation was supported in part by Grant CA15883 awarded by the National Cancer Institute and by Grant AG0003 awarded by the National Institute of Aging.

² Present address: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore City Hospitals, Baltimore Regional Burn Center, 4940 Eastern Avenue, Baltimore, Md. 21224.

Received 6/21/77. Accepted 1/30/78.