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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005216-26
Application #
6160876
Study Section
Special Emphasis Panel (LTIB)
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Nesterova, M; Johnson, N; Cheadle, C et al. (2006) Autoantibody biomarker opens a new gateway for cancer diagnosis. Biochim Biophys Acta 1762:398-403
Cho-Chung, Yoon S (2006) Autoantibody biomarkers in the detection of cancer. Biochim Biophys Acta 1762:587-91
Nesterova, Maria V; Cho-Chung, Yoon S (2004) Antisense protein kinase A RIalpha inhibits 7,12-dimethylbenz(a)anthracene-induction of mammary cancer: blockade at the initial phase of carcinogenesis. Clin Cancer Res 10:4568-77
Cho-Chung, Yoon S (2004) Antisense protein kinase A RI alpha-induced tumor reversion: portrait of a microarray. Biochim Biophys Acta 1697:71-9
Cho-Chung, Yoon S (2003) CRE-enhancer DNA decoy: a tumor target-based genetic tool. Ann N Y Acad Sci 1002:124-33
Mani, S; Goel, S; Nesterova, M et al. (2003) Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I. Ann N Y Acad Sci 1002:252-62
Cho-Chung, Yoon S; Becker, Kevin G (2003) A genome-wide view of antisense. Nat Biotechnol 21:492
Cho-Chung, Yoon S (2003) Antisense DNAs as targeted genetic medicine to treat cancer. Arch Pharm Res 26:183-91
Cho-Chung, Yoon S (2003) cAMP signaling in cancer genesis and treatment. Cancer Treat Res 115:123-43
Cho, Yee Sook; Cho-Chung, Yoon S (2003) Antisense protein kinase A RIalpha acts synergistically with hydroxycamptothecin to inhibit growth and induce apoptosis in human cancer cells: molecular basis for combinatorial therapy. Clin Cancer Res 9:1171-8

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