CYCLIC AMP DEPENDENT PROTEIN KINASE ISOFORMS AND GROWTH CONTROL

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The use of site-selective cAMP analogs greatly advanced our understanding of the mechanism of cAMP action in growth control. It was discovered that site-selective cAMP analogs can act as novel biological agents capable of inducing growth inhibition and differentiation in a broad spectrum of human cancer cell lines, including carcinomas, sarcomas, and leukemias, without causing cytotoxicity. 8-Cl-cAMP, the most potent site-selective cAMP analog, was selected as a preclinical Phase I antineoplastic agent of the National Cancer Institute (January 27, 1988). A Phase I clinical study of 8-Cl-cAMP has been completed at a foreign Institute (Clin Cancer Res I, 377-384,1995). Significantly, this was the first demonstration that a cAMP analog can induce its biological effect at micromolar concentrations-the physiological concentration of cAMP, as opposed to the millimolar pharmacological or cytotoxic concentrations of cAMP analogs reported in all previous literature. The discovery rendered a critical assessment that the potency of a cAMP analog in growth inhibition depends on the analog's ability to selectively modulate the RI and RII regulatory subunits of cAMP-dependent protein kinase precisely, down-regulation of RI-alpha with up-regulation of RII-beta leading to the restoration of the normal balance of these cAMP transducing proteins in cancer cells. The use of antisense strategy and retroviral vector-mediated gene transfer technology provided direct evidence that two isoforms, the RI-alpha and RII-beta regulatory subunits of cAMP-dependent protein kinase, have opposite roles in cell growth and differentiation; RI-alpha being growth stimulatory while RII-beta is a growth-inhibitory and differentiation-inducing protein. As RI-alpha expression is enhanced during chemical or viral carcinogenesis, in human cancer cell lines, in primary human tumors, and in multidrug-resistant (MDR) cancer cells as opposed to non-MDR parental cells, it is a target for cancer diagnosis and therapy.