Further studies on the inhibition of chemical carcinogenesis by Corynebacterium parvum

Abstract

The conditions under which administration of Corynebacterium parvum (CP) inhibits the development of tumours in response to methylcholanthrene (MC) have been further delineated. After subcutaneous (SC) injection of a single large dose of MC in solution (0.5 mg to CBA mice, 0.25 mg to BALB/c), repeated intravenous (IV) injection of CP starting 4 days before injection of the carcinogen delays or prevents the development of fibrosarcomas, whereas a similar course of injections starting 4 weeks later, and single injections of CP at various times, have little or no inhibitory effect. After injection of only 0.1 mg MC repeated injection of CP, even when started before injection of carcinogen, is ineffective. Carcinogenesis may also be inhibited by repeated IV injection of CP starting 4 days before implantation of Millipore discs impregnated either with MC alone or with a mixture of MC and paraffin wax. In untreated mice SC implantation of a disc impregnated with 0.1 mg MC was more strongly carcinogenic than SC injection of the same quantity of MC in solution. The effect of CP depended on the site of implantation, the type of disc and the regimen of CP administration. With MC wax discs implanted in the peritoneal cavity the development of tumours was completely prevented by repeated administration of CP starting before insertion of the disc. Similar treatment resulted in more modest inhibition of carcinogenesis after SC implantation of MC wax discs and MC discs of small pore size. In previous papers three possible mechanisms have been suggested to account for the inhibitory effect of CP on chemical carcinogenesis by MC: (1) destruction of transformed cells by CP-activated macrophages; (2) accelerated conversion of the MC to completely non-carcinogenic substances; and (3) inhibition of the conversion of MC to a highly carcinogenic epoxide. The present results do not exclude any of these possibilities but the observation that single injections of CP have little effect suggests that modification of the metabolism of MC is not the whole explanation. The different results obtained with carcinogenic discs implanted in different sites, and with different types of disc, are attributed to differences in the degree of macrophage activation and in the extent to which activated macrophages made effective contact with the carcinogen and with developing tumour cells. Two possible explanations of the failure of repeated injection of CP to reduce the incidence or rate of development of tumours in response to injection of only 0.1 mg MC are suggested.