SITE-SELECTIVE CAMP ANALOGS AS ANTINEOPLASTICS AND CHEMOPREVENTIVES

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Cyclic AMP (cAMP) in mammalian cells functions by binding to cAMP receptor protein, the regulatory subunit of cAMP-dependent protein kinase. The cAMP receptor protein has two different cAMP binding sites, and cAMP analogs that selectively bind to either one of the two binding sites are known as Site 1-selective (C-2 and C-8 analogs) and Site 2-selective (C-6 analogs), respectively. Such site-selective cAMP analogs at micromolar concentrations exerted potent growth inhibition, with no sign of toxic effects, in a spectrum of human cancer cell lines, including those that are resistant to previously tested cAMP analogs, leukemia lines, v-ras-H oncogene-transformed NIH/3T3 cells, and v-ras(Ki) oncogene-or TGFalpha-transformed normal rat kidney (NRK) cells; the combination of a C-8 with a C-6 analog showed synergistic effects. The growth inhibition was not due to a block in a specific phase of cell cycle but paralleled selective modulation of type I versus type II protein kinase isozymes, suppression of cellular protooncogene expression, inhibition of TGFalpha production, phenotypic change, and differentiation (leukemic cells). It is suggested that the site-selective cAMP analogs, substituting for endogenous cAMP and binding to protein kinase, suppress the cancer cell growth not via directly inhibiting cell division but rather by promoting cell differentiation. Site-selective cAMP analogs thus provide new biological tools for investigating cell proliferation and differentiation and also for the improved management of human cancer. 8-C1-cAMP is now in preclinical phase I studies at the National Cancer Institute. A U.S. patent for the cAMP analogs, entitled "Derivatives of cyclic AMP as treatment for cancer," was applied for on May 25, 1988.