Inhibition of nitroso chemical carcinogen activation of rat hepatic guanylate cyclase by anticancer agents

Abstract

Recent studies have demonstrated that nitroso chemical carcinogens activate guanylate cyclase (EC 4.6.1.2) which catalyzes the production of guanosine 3',5'-monophosphate. This nucleotide is thought to be involved in normal and abnormal cell growth. We examined the effect of 3 major classes of anticancer chemotherapeutic agents, the antimetabolites (methotrexate and 6-mercaptopurine), antitumor antibiotics (adriamycin and actinomycin D), and alkylating agents (cytoxan, uracil mustard, isophosphamide, chlornaphazine, and 1-propranol-3,3'-iminodimethane sulfonate) on the activation of guanylate cyclase by nitroso chemical carcinogens. The anticancer chemotherapeutic agents noncompetitively blocked the activation of rat hepatic guanylate cyclase by N'-nitro-N-nitroso-N-propylguanidine (NNPG) and hydrazine. Adriamycin, methotrexate, and uracil mustard were the most effective inhibitors completely abolishing the effect of 1 mM NNPG on guanylate cyclase activity. The remainder of the anticancer chemotherapeutic agents abolished the NNPG activation of guanylate cyclase 40--70%. Since a previously described guanylate cyclase inhibitor has been shown to terminate the growth of an undifferentiated prostatic cancer in tissue culture the present data may indicate that one of the mechanisms by which anticancer chemotherapeutic agents exert their effects is by inhibition of tumor guanylate cyclase activity.