<i>In vitro</i> measurement of carcinogen‐resistant liver cells during hepatocarcinogenesis

Laishes, Brian A.; Ea, Roberts; Farber, Emmanuel

doi:10.1002/ijc.2910210210

Cited by 48 publications

(12 citation statements)

References 19 publications

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“…This phenotypic property is obvious both irz viw, when nodule-bearing animals arc treated with different toxic substances (32,89), and itt vitro by treating nodular cells in tissue culture (13,14,48). The biological significance of this tolerance to xenobiotic substances is not known in detail, but in the hepatocarcinogenic protocols where mitoinhibitory or other toxic drugs are used in the promotion phase, the resistance certainly seems to be important, permitting the selective proliferation of initiated cells to foci and hepatocyte nodules.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Xenobiotics in Hepatocyte Nodules

et al. 1987

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Section: Introductionmentioning

confidence: 99%

Metabolism of Xenobiotics in Hepatocyte Nodules

et al. 1987

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“…Numerous studies have shown that HNs with similar morphologic and biochemical properties are produced following exposure of rats to any of a variety of different carcinogens (10)(11)(12)(13)(14)(15)(16). Moreover, these carcinogen-induced changes in HNs are associated with the development of resistance to many structurally diverse hepatotoxins (10)(11)(12)(13)(14)(15)(16), prompting Farber to use the term "resistant hepatocyte model" in describing this system (16). The induction of stable levels of an anionic GSHTase isoenzyme in HNs resistant to various hepatotoxins, and in DoxR cells resistant to many naturally occurring antineoplastic agents, prompted us to compare the biochemical changes in these two models in more detail.…”

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confidence: 99%

Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats.

Cowan

Batist

Tulpule

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

223

130

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MCF7 human breast cancer cells selected for resistance to doxorubicin (adriamycin; DoxR) have developed the phenotype of multidrug resistance. Multidrug resistance in DoxR MCF7 cells (called AdrR MCF7 cell line in previous publications) is associated with biochemical changes similar to those induced by carcinogens in rat hyperplastic liver nodules (HNs) and associated with resistance to xenobiotics in that system. In HNs and DoxR cells, exposure to a single agent results in the selection of cells that are cross-resistant to a wide variety of structurally dissimilar toxic agents. Resistance in both systems is associated with decreases in intracellular accumulation of toxins and changes in phase I (decreased cytochrome P1-450) and phase H (increased glutathione transferase and glucuronyltransferase) drug-metabolizing activities. In HNs and DoxR cells, resistance is associated with the induction of relatively stable levels of an immunologically related anionic glutathione transferase isozyme (EC 2.5.1.18). The rmding of similar biochemical changes associated with the development of resistance to various xenobiotics in HNs and to many naturally occurring antineoplastic agents and at least one carcinogen (benzo[a]pyrene) in DoxR MCF7 cells suggests that the mechanisms of resistance in these two models may be similar.

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“…Chronic or recurrent necrosis of hepatic cells can result in regenerative stimuli and be a mechanism of tumor promotion (38). Hepatic cells initiated by DEN may also be resistant to the effects of cytotoxic chemicals such as 3,3',4,4',5,5'-HBB and have an increased responsiveness to endogenous or exogenous growth stimuli (39,40). It is our contention that it is important to distinguish between tumor promoters that can exert effects at noncytotoxic doses and those that can only promote as a secondary effect of hepatic necrosis.…”

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Effects of PCBs and related compounds on hepatocarcinogenesis in rats and mice.

Sleight¹

1985

Environ Health Perspect

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Commercial mixtures of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) can cause hepatocellular carcinoma in rats and mice. Present evidence indicates that these chemicals act as promoters and not initiators of hepatocarcinogenesis. Our results show that Firemaster BP-6 (FM) and its nontoxic major congener, 2,2',4,4',5,5'-hexabromobiphenyl (HBB), act as promoters in the two-stage model for hepatocarcinogenesis devised by Pitot and associates. A toxic congener, 3,3',4,4',5,5'-HBB, also was assessed for tumor-promoting activity. This congener, though not in FM, is similar to TCDD, in that both cause 3-methylcholanthrene (MC)-type induction of hepatic microsomal enzymes and produce similar toxic responses. FM contains several congeners which are mixed-type inducers in that they induce MC-type and phenobarbital (PB)-type enzymes. The toxicity of FM is most likely associated with its congeners which are mixed-type inducers and not to relatively nontoxic congeners such as 2,2',4,4',5,5'-HBB which are strictly PB-type inducers. Congener 3,3',4,4',5,5'-HBB acted as a tumor promoter only at a dose that was hepatotoxic. A synergistic effect on tumor promoting ability was produced by combining a nontoxic and nonpromoting dose of 3,3',4,4',5,5'-HBB with a promoting dose of 2,2',4,4',5,5'-HBB. Our results suggest that synergism between toxic and nontoxic congeners in FM may explain why mixtures such as FM have greater promoting ability than individual congeners. Our results also indicate that with PBB, toxicity and carcinogenicity are not necessarily related.One of the major concerns of people exposed to environmental chemicals such as polychlorinated biphenyls (PCBs) is whether or not these chemicals are carcinogenic. Although epidemiologic studies have not conclusively shown a greater cancer risk for people as a result of PCB exposure, there is conclusive evidence that PCBs can cause hepatic cancer in rodents. Prolonged dietary administration of PCB mixtures has induced hepatic tumors in rats (1-4) and mice (5-7). Hepatocellular carcinomas were described in each species and, in addition, what are classified as neoplastic nodules and foci of cellular alteration were described (8).Evidence to date strongly indicates that the mixtures of PCBs act as promoters of hepatic carcinogenesis. When PCBs were given to rats after an initiator such as diethylnitrosamine there was convincing evidence that they had a tumor promoting effect in the liver (9,10).Thmor promotion was also evident when impurities such as dibenzofurans were removed from the PCB mixture (10). Earlier, Kimura et al. (11) reported a high incidence of hepatocellular carcinomas in the livers of rats fed a diet containing a tumor initiator, 3'-methyl-4-dimethylaminoazobenzene, for 2 months followed by dietary administration of Kanechlor 400, a commercial *Department of Pathology, Michigan State University, East Lansing, MI 48824. mixture of PCBs, for 6 months. Since administration of the initiator by itself or administration of Kanechlor before o...

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In vitro measurement of carcinogen‐resistant liver cells during hepatocarcinogenesis

Cited by 48 publications

References 19 publications

Metabolism of Xenobiotics in Hepatocyte Nodules

Metabolism of Xenobiotics in Hepatocyte Nodules

Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats.

Effects of PCBs and related compounds on hepatocarcinogenesis in rats and mice.

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