MODIFYING INFLUENCE OF PRIOR TREATMENT WITH TOXIC AGENTS ON INDUCTIONOF PRENEOPLASTIC AND NEOPLASTIC LESIONS IN A MEDIUM-TERM MULTIORGAN CARCINOGENESIS BIOASSAY

The modifying potential of prior administration of toxic agents was in vestigated in our multi-organ carcinogenesis model using male F344/DuC rj rats with the aim of assessing the link between tissue damage and i nitiation. Animals were administered one of four toxic agents for 8 wk , and then treated with N-diethylnitrosamine (DEN, 100 mg/kg body weig ht (b.w.), intraperitoneally (i.p.), single injection), N-methylnitros ourea (MNU, 20 mg/kg b.w., i.p., four times during wk 9 and 10), and d ihydroxy-di-N-propylnitrosamine (DHPN, 0.1% in drinking water, during wk 11 and 12) for multi-organ carcinogenesis. All surviving rats were killed at the end of wk 36, and the major organs carefully examined fo r preneoplastic and neoplastic lesion development. Immunohistochemical demonstration of glutathione S-transferase placental form (GST-P) pos itive foci was also performed to facilitate quantitative assessment of liver lesion development. D-galactosamine (300 mg/kg b.w., i.p., once a week), a hepatotoxin, significantly inhibited the induction of GST- P positive foci, while 4,4'-diaminodiphenylmethane (DDPM, 0.1% in diet ), a bile duct proliferator which is itself a hepatocarcinogen, posses sed enhancing activity. DDPM, also a goitrogen, clearly inhibited the development of follicular cell tumors in the thyroid. Uracil (3.0% in diet), which is an inducer of papillomatosis in the urinary bladder, d id not exert any enhancing potential on bladder carcinogenesis. Bleomy cin (2 mg/kg b.w., i.p., twice a week), which is an alveolar epitheliu m injuring agent, also did not modify the induction of alveolar epithe lium proliferative lesions. These results indicate that prior organ in jury by toxic agents does not always act to enhance sensitivity to car cinogenesis. (C) 1993 Wiley-Liss, Inc.