ANTICARCINOGENIC EFFECT OF N6,O2'-DIBUTYRYL CYCLIC ADENOSINE 3'-5'-MONOPHOSPHATE ON 7,12-DIMETHYLBENZ(A)ANTHRACENE MAMMARY-TUMOR INDUCTION IN THE RAT AND ITS RELATIONSHIP TO CYCLIC ADENOSINE 3'-5'-MONOPHOSPHATE METABOLISM AND PROTEIN-KINASE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (6) , 2736-2740
Abstract
A single intubation of 7,12-dimethylbenz(a)anthracene (DMBA) (20 mg in 1 ml sesame oil) to female Sprague-Dawley rats at 50 days of age produces primary mammary carcinomas in 80% of rats of 100-150 days of age. Administration of N6,O2''-dibutyryl cAMP (DBcAMP) orally beginning at 1 day prior to DMBA intubation resulted in marked delay and reduction of tumor production: only 15% as many DBcAMP-treated rats had tumors as in the control group (DMBA only) with 60 days of delay in the 1st tumor appearance. DMBA-induced tumor production was preceded by changes in the cAMP metabolism and protein kinase of the mammary gland. Within 24 h post-DMBA intubation, the intracellular cAMP level and adenylate cyclase activity increased with an increase in type I isozyme of cAMP-dependent protein kinase, a form which has been associated with increased proliferative activity and a less differentiated cellular state in other tissues. The increases in cAMP level, adenylate cyclase activity, and the protein kinase activity were transient, and the values decreased to below the control values by day 10 post-DMBA intubation. In mammary glands of rats that had received DBcAMP, the cAMP level and protein kinase isozyme pattern were similar to those of older rats that are no longer susceptible to the carcinogen. The inhibitory effect on DMBA-induced carcinogenesis may be related to the modifications that DBcAMP induces on cAMP level, adenylate cyclase activity, and cAMP-dependent protein kinase of the mammary gland.

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