CHEMOPREVENTIVE PROPERTIES AND MECHANISMS OF N-ACETYLCYSTEINE - THE EXPERIMENTAL BACKGROUND

The thiol N-acetylcysteine (NAG), now under clinical trial for cancer chemoprevention both in Europe (project Euroscan) and in the US (Natio nal Cancer Institute), has been shown during the past decade to exert protective effects in a variety of experimental test systems. NAC inhi bited spontaneous mutagenicity and that induced by a number of chemica l compounds and complex mixtures. Moreover, NAC significantly decrease d the incidence of neoplastic and preneoplastic lesions induced by sev eral chemical carcinogens in rodents (mice, rats, hamsters), e.g., in lung, trachea, colon, liver, mammary gland, Zymbal gland, bladder and skin. Our studies provided evidence that multiple mechanisms contribut e to NAC antimutagenicity and anticarcinogenicity. They include extrac ellular mechanisms, such as detoxification of reactive compounds due t o the nucleophilic and antioxidant properties of NAG, inhibition of ni trosation products, and enhancement of thiol concentration in intestin al bacteria; trapping and enhanced detoxification of carcinogens in lo ng-lived non-target cells, such as erythrocytes and bronchoalveolar la vage cells; mechanisms working in the cytoplasm of target cells, such as replenishment of GSH stores, modulation of metabolism of mutagens/c arcinogens, blocking of electrophiles, and scavenging of reactive oxyg en species; and nuclear effects, such as inhibition of DNA adduction b y metabolites of carcinogens, inhibition of ''spontaneous'' mutations, attenuation of carcinogen-induced DNA damage, and protection of nucle ar enzymes, such as poly(ADP-ribose) polymerase. In particular, benzo( a)pyrene diolepoxide-DNA adducts in rats exposed either to benzo(a)pyr ene or cigarette smoke were prevented by NAC not only in target organs far carcinogenicity, such as lung and trachea, but also in other orga ns, such as heart, aorta and testis, where these molecular biomarkers have been tentatively associated with cardiomyopathies, atherosclerosi s and hereditary diseases, respectively. The protective mechanisms of NAC are expected to affect not only initiation but also promotion and progression, due to the reiterate involvement of: certain key mechanis ms in carcinogenesis. Moreover, recent studies demonstrate that NAC ca n also affect the steps of invasion and metastasis, including the spec ific inhibition of type TV collagenases degrading basement membranes, inhibition of chemotactic and invasive activities of human and murine malignant cells, delay of primary tumor formation in mice, and inhibit ion of lung metastases. Evidence was also provided that administration of pharmacological doses of NAC sharply decreases urinary excretion o f mutagens in smokers. (C) 1995 Wiley-Liss, Inc.