title: Induced drug resistance inhibits selection of initiated cells and cancer development.
abstract: Compounds exerting a mitoinhibitory effect on normal hepatocytes are potent promoters in the resistant hepatocyte model of chemical carcinogenesis in combination with stimulation of regenerative growth by partial hepatectomy or treatment with carbon tetrachloride. 2-Acetylaminofluorene (2-AAF) almost completely inhibits liver cell regeneration after partial hepatectomy, allowing only resistant cells to participate in regenerative growth. After initiation by diethylnitrosamine and promotion with 2-AAF and partial hepatectomy (PH), focal growth of initiated cells generates liver lesions which occupy 40% of the hepatic volume three weeks after PH. In this work the mechanism for the anti promoting effects of phenobarbital and 3-methylcholantrene were investigated as well as their effects on the development of malignant hepatocellular carcinoma in the resistant hepatocyte model. Treatment with phenobarbital or, especially, 3-methylcholanthrene rendered normal rat hepatocytes resistant to the mitoinhibitory effect of 2-AAF. In combination with 2-AAF/PH, 3-methylcholanthrene shortened the regenerative growth period to less than one week. In the Solt-Farber protocol for experimental hepatocarcinogenesis, treatment with phenobarbital or 3-methylcholanthrene during promotion with 2-AAF/PH permitted hepatocytes surrounding the focal lesions to respond with regenerative growth. The foci and surrounding liver grew until the liver/body mass index reached the control value. With phenobarbital treatment the total focal volume was 20% of the liver volume three weeks after PH, whereas the corresponding value in the case of 3-methylcholanthrene was only 1%. Labelling index data supported the conclusion that growth of the liver lesions in the resistant hepatocyte model was dependent on differential inhibition of normal hepatocyte growth by the promoter and that the size of the foci obtained was related to the length of time after PH required to complete liver regeneration. 3-methylcholanthrene induced 2-AAF resistance prevented the development of large persistent nodules and hepatocellular carcinoma while phenobarbital delayed cancer development with several month. The data thus supports the idea that the degree of clonal expansion during promotion determines the size of the population at risk for malignant transformation, as well as the final frequency of carcinomas.
authors.affiliation: Department of Immunology, Microbiology, Pathology and Infectious Diseases, Karolinska Institutet, Huddinge University Hospital, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Rissler
authors.forename: U B
authors.initials: UB
authors.lastname: Torndal
authors.forename: L C
authors.initials: LC
authors.lastname: Eriksson
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002273:Carcinogens; D008748:Methylcholanthrene; D015073:2-Acetylaminofluorene; D010634:Phenobarbital