8-Chloroadenosine-3',5'-cyclic-monophosphate (8-Cl-cAMP), an analog of c-AMP, is a novel antineoplastic agent. It has been shown to be effective against different human cancer cell lines modulating the cellular signal transduction pathway, thereby causing growth inhibition, cell differentiation, and apoptosis. 8-Cl-cAMP preferentially binds to the R2 subunit of protein kinase A (PKA) and induces rapid R2 up-regulation and eventual R1 subunit down-regulation. It has potent inhibitory effects on a wide variety of human cancer cell lines, with an IC50 ranging from 0.1 to 20 uM. The IC50 falls with the length of drug exposure. It can suppress c-myc and c-ras proto-oncogenes in vitro and in vivo. It was shown that 8-Cl-cAMP induces cell growth inhibition through AMP-activated protein kinase (AMPK) activation with p38 MAPK acting downstream of AMPK in this signaling pathway. 8-Cl-cAMP induced apoptosis, apparently through activation of the p38 MAPK pathway by inducing progressive phosphorylation of the p38 mitogen-activated protein kinase (MAPK), via activation of AMPK by its metabolite 8-Cl-adenosine. 8-Cl-cAMP does not significantly inhibit the growth of NIH 3T3 cells, rat kidney fibroblasts, mammary epithelial cells, or peripheral blood lymphocytes, nor does it inhibit the growth of parental cells whose progeny have been transformed. Such selectivity makes it an attractive candidate for cancer therapy suggesting that it should not cause the toxicity of conventional cytotoxic agents but should inhibit tumor growth. 8-Cl-cAMP has been evaluated in phase I/II clinical trials.