Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Croy, Robert G.

doi:10.1289/ehp.93101s5289

Cited by 17 publications

(10 citation statements)

References 64 publications

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“…As a working hypothesis, we, therefore, assumed that ragaglitazar caused urothelial cancers in rats by a receptor-mediated effect of the parent compound (mechanism (i) above), which may be exacerbated by a cytotoxic effect of parent compound or metabolites on urothelium, promoting a chronic wound healing response (mechanism (iii) above). This mode of action hypothesis ( Figure 3 ), comprising 2 nonexclusive mechanisms ( Figure 1(b) , (i) and (iii)) was in agreement with coexpression of PPAR α and γ by the urothelium [ 17 , 18 , 38 ], with the known propensity of various PPAR agonists to exhibit cytotoxic effects [ 36 , 61 , 62 ], and with the known positive correlation between cytotoxic and carcinogenic effects for some small molecule drugs [ 63 , 64 ]. Similarly, it was concluded for naveglitazar-induced bladder cancer in rats that a mechanism involving a direct effect of the compound on PPARs in the urothelium should be considered [ 31 ].…”

Section: Ranking the Possible Mechanisms For The Carcinogenic Effesupporting

confidence: 57%

Rat Urinary Bladder Carcinogenesis by Dual‐Acting PPARα + γ Agonists

et al. 2008

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Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

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Section: Ranking the Possible Mechanisms For The Carcinogenic Effesupporting

confidence: 57%

Rat Urinary Bladder Carcinogenesis by Dual‐Acting PPARα + γ Agonists

et al. 2008

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“…Nephrotoxic chemicals can lead to renal tumor formation by causing chronically sustained cytotoxicity accompanied by compensatory cell regeneration (Hard, 1998). Although the precise mechanism is not yet elucidated, it is generally accepted that persistent cell proliferation of a compensatory nature is a risk factor for tumor development (Butterworth and Goldsworthy, 1991;Cohen, 1995;Croy, 1993;Foster, 1997;Moore and Tsuda, 1998;Preston-Martin et al, 1990). Chloroform has become the classic nongenotoxic example of chem-icals acting to produce renal tubule tumors in rats and mice via this mode of action (Butterworth et al, 1995).…”

Section: Sustained Cytotoxicity and Cell Regenerationmentioning

confidence: 99%

Significance of the Renal Effects of Ethyl Benzene in Rodents for Assessing Human Carcinogenic Risk

Hard¹

2002

Toxicological Sciences

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In the two-year carcinogenicity study conducted by the National Toxicology Program (NTP) and reported in 1999, ethyl benzene administered by inhalation to Fischer 344 rats was associated with an increase in renal tubule tumors in males after standard evaluation of a single section of each rat's kidney, and in both males and females after evaluation of step-sectioned kidney. In the present study, the kidneys of all rats in the NTP bioassay were histopathologically reevaluated with the purpose of attempting to define a mode of action underlying the development of the renal tumors. In the reevaluation, the increases in renal tubule tumor incidence in the high-dose groups exposed to 750 ppm were confirmed, as well as increases in the precursor lesion, atypical tubule hyperplasia (ATH). The vast majority of the proliferative lesions were of basophilic type and, apart from three carcinomas in the high-dose males, either small adenomas or foci of ATH. There was also a marked exacerbation by the chemical of chronic progressive nephropathy (CPN), an age-related spontaneous disease involving both degenerative and regenerative components, in the high-dose males exposed to 750 ppm of ethyl benzene (68% of high-dose males with end-stage CPN versus 12% of control males), and a modest exacerbation in the high-dose females (8% of high dose versus 0% of controls). Almost all of the basophilic tumors occurred in rats with advanced, usually end-stage, CPN, and they were located in areas of parenchyma involved in the CPN disease process. Statistical analysis of the proliferative lesion and CPN data revealed a highly significant correlation between ATH/renal tumor incidence and end-stage CPN, and adjusting for end-stage CPN removed any statistically significant difference in renal tumor incidence between treated groups and controls. Careful examination of renal tubules revealed no evidence of renal tubule injury or increased mitotic activity that would support sustained cytotoxicity/cell regeneration as a mode of action for tumor development. An absence of granular casts and linear papillary mineralization discounted the possibility of alpha(2u)-globulin nephropathy as the primary underlying basis in male rats, even though subchronic studies revealed a modest accumulation of hyaline droplets in proximal tubules. Based on the close association of ATH and renal tumors with CPN, it was concluded that chemically induced exacerbation of CPN was the mode of action underlying the development of renal neoplasia, a pathway that is considered to have no relevance for extrapolation to humans.

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“…It is well known that increased rates of cell proliferation can escalate the risk of malignancy following exposures to chemical agents [89]. Since the knowledge about the mechanisms and effects of various genotoxic agents is critical to human health, the analysis of chromosomes in interphase cells seems to be extremely important in genotoxicity studies.…”

Section: Genotoxicity Of Exposure To Chemical Agentsmentioning

confidence: 99%

The use of premature chromosome condensation to study in interphase cells the influence of environmental factors on human genetic material

Hatzi

Terzoudi

Paraskevopoulou

et al. 2006

The Scientific World JOURNAL

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Nowadays, there is a constantly increasing concern regarding the mutagenic and carcinogenic potential of a variety of harmful environmental factors to which humans are exposed in their natural and anthropogenic environment. These factors exert their hazardous potential in humans' personal (diet, smoking, pharmaceuticals, cosmetics) and occupational environment that constitute part of the anthropogenic environment. It is well known that genetic damage due to these factors has dramatic implications for human health. Since most of the environmental genotoxic factors induce arrest or delay in cell cycle progression, the conventional analysis of chromosomes at metaphase may underestimate their genotoxic potential. Premature Chromosome Condensation (PCC) induced either by means of cell fusion or specific chemicals, enables the microscopic visualization of interphase chromosomes whose morphology depends on the cell cycle stage, as well as the analysis of structural and numerical aberrations at the G1 and G2 phases of the cell cycle. The PCC has been successfully used in problems involving cell cycle analysis, diagnosis and prognosis of human leukaemia, assessment of interphase chromosome malformations resulting from exposure to radiation or chemicals, as well as elucidation of the mechanisms underlying the conversion of DNA damage into chromosomal damage. In this report, particular emphasis is given to the advantages of the PCC methodology used as an alternative to conventional metaphase analysis in answering questions in the fields of radiobiology, biological dosimetry, toxicogenetics, clinical cytogenetics and experimental therapeutics.

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Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Cited by 17 publications

References 64 publications

Rat Urinary Bladder Carcinogenesis by Dual‐Acting PPARα + γ Agonists

Rat Urinary Bladder Carcinogenesis by Dual‐Acting PPARα + γ Agonists

Significance of the Renal Effects of Ethyl Benzene in Rodents for Assessing Human Carcinogenic Risk

The use of premature chromosome condensation to study in interphase cells the influence of environmental factors on human genetic material

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