Arrest of hormone-dependent mammary cancer growth in vivo and in vitro by cholera toxin.

Growth of 7,12-dimethylbenz(alpha)anthracene-induced mammary carcinoma in rat was arrested by daily s.c. injections of cholera toxin. At a dose of 2 micrograms/200-g rat, tumors regressed to 50% of their initial size within 2 weeks, and 85% of tumors regressed completely within 4 to 5 weeks. The same response to cholera toxin was observed with another hormone-dependent mammary tumor, MTW9, but not with the hormone-independent tumors, DMBA No. 1 and MT 13762. The latter result was consistent with the lack of response of these hormone-independent tumors to hormone removal (ovariectomy) or N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate treatment. The growth-inhibitory effect of cholera toxin was dose dependent, and upon cessation of treatment tumors resumed growth; after complete regression, however, tumors did not reappear until 6 months after termination of the treatment. An amount of cholera toxin as high as 10 micrograms/day/200-g rat s.c. injected over a 6-week period showed no systemic toxicity in the animals. The growth of human breast cancer cells (MCF-7) in culture was also inhibited by a daily supplement of cholera toxin. At a concentration of 100 ng/ml, the cell replication ceased completely within 2 days. The growth inhibitions, both in vivo and in vitro, were accompanied by marked increases in the cellular cyclic adenosine 3':5'-monophosphate content and type II cyclic adenosine 3':5'-monophosphate-dependent protein kinase activity as well as a decrease of estrogen binding activity. Thus, extinction of mammary cancer can be achieved by cholera toxin, an agent that stimulates the intracellular cyclic adenosine 3':5'-monophosphate system.