Differentiation therapy of cancer targeting the ri-alpha regulatory subunit of cAMP-dependent protein-kinase (review).

Consideration of the cancer process as a problem of blocked ontogeny makes attractive the approach to the control of cancer through differentiation therapy. The use of antisense strategy and retroviral vector-mediated gene transfer technology provided direct evidence that two isoforms of cAMP receptor protein, the RI and RII regulatory subunits of cAMP-dependent protein kinase, have opposite, roles in cell growth and differentiation, RI being growth stimulatory while RII is a growth-inhibitory and differentiation-inducing protein. As RIalpha expression is enhanced during cell transformation, and in primary human tumors and cancer cell lines as compared to their normal counterparts, it is an attractive target for cancer treatment. 8-Cl-cAMP and RIalpha antisense oligodeoxynucleotide, those that effectively down-regulate RIalpha and upregulate RIIbeta without producing cytotoxicity, provide new approaches toward differentiation therapy of cancer.