An analysis of in vivo hprt mutant frequency in circulating T-lymphocytes in the normal human population: a comparison of four datasets

Robinson, Derek; Goodall, Kevin; Albertini, Richard J.; O’Neill, J. Patrick; Finette, Barry A.; Sala-Trepat, M.; Moustacchi, E.; Tates, A.D.; Beare, David; Green, Michael H.L.; Cole, Jane

doi:10.1016/0165-1161(94)90053-1

Cited by 110 publications

(51 citation statements)

References 30 publications

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“…In at-risk populations including smokers, patients with DNA repair deficiency syndromes, and atom bomb survivors there are significant mutations in the HPRT locus that directly corresponds with higher cancer incidence (Branda, O"Neill, Jacobson-Kram, & Albertini, 1992;Cheng et al, 1995;Duthie, Ross, & Collins, 1995;Hakoda, Akiyama, Kyoizumi, & Awa, 1988;Hou et al, 1999;Robinson et al, 1994;Sawada et al, 1998;Tates, Dam, Natarajan, Zwinderman, & Osanto, 1994). While its role as a standard mutational biomarker for cancer development has been well established, the relevance of HPRT to the proliferative capacity and tumorigenesis of cancer has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Elevated Expression of Hypoxanthine Guanine Phosphoribosyltransferase within Malignant Tissue

Townsend¹,

Felsted²,

Ence³

et al. 2017

CCO

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Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) is a housekeeping enzyme involved in the purine synthesis of guanine and inosine in the salvage pathway. While other salvage pathway enzymes, such as TK1, have been established as biomarkers for both cancer cell proliferation and cancer development, little research been done to evaluate whether HPRT has the same potential as a cancer biomarker. We designed this study to determine if HPRT has value as an identifier of malignancy within the most common types of cancer. We utilized histological samples from lung, colon, prostate, and breast cancer with additional normal tissue to evaluate whether there was any elevation of HPRT within malignant samples. In addition, we also assessed general HPRT expression within patient"s samples from The Cancer Genome Atlas (TCGA) to confirm clinical relevance. We found that within a subset of patients, there was significant elevation of HPRT when compared to normal tissue controls. This elevation was seen in 33-55% of the malignant samples and appears to have no dependence on cancer stage. There were slight differences in staining patterns among all the organ types, but overall each organ displayed the same pattern of "HPRT high" and "HPRT low" populations within malignant samples. We found that in our TCGA samples, there was a similar elevation of HPRT that was significant when compared to normal controls. Overall, as an upregulated enzyme that does not directly correlate with stage, HPRT could become a valuable marker in the early diagnosis of a variety of solid tumors.

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Section: Introductionmentioning

confidence: 99%

Elevated Expression of Hypoxanthine Guanine Phosphoribosyltransferase within Malignant Tissue

Townsend¹,

Felsted²,

Ence³

et al. 2017

CCO

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show abstract

Section: Biologically Based (Mvk) Modeling To Bound Moa Uncertaintymentioning

confidence: 99%

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

Bogen¹

2007

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A relatively simple, quantitative approach is proposed to address a specific, important gap in the approach recommended by the USEPA Guidelines for Cancer Risk Assessment to address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate "linear" (genotoxic) vs. "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach-similar to that used in reference dose procedures for classic toxicity endpoints-can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a "nonlinear" toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen.Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2-and 1,4-naphthoquinone.Bound-specific "adjustment" factors were then used to reduce naphthalene risk estimated by linear extrapolation (under the default genotoxic MOA assumption), to account for the DMOA exhibited by this compound.3

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“…Biologically plausible values for m 0 were presumed to be between 10 -8 and 10 -7 y -1 , i.e., similar to estimated values pertaining to humans (Trainor et al, 1984;King et al, 1994;Mendelsohn, 1990;Robinson et al, 1994). The background rate b 0 of stem-cell division for nasal epithelium was assumed to be 1 y -1 , based on labeling indices <1% observed in basal lamina that serve as stem-cell reservoirs for rat nasal epithelial tissues Hotchkiss et al, 1997).…”

Section: Biologically Based (Mvk) Modeling To Bound Moa Uncertaintymentioning

confidence: 99%

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

Bogen¹

2007

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As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate "linear" (genotoxic) vs. "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach-similar to that used in reference dose procedures for classic toxicity endpoints-can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a "nonlinear" toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rattumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2-and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding "uncertainty" factor <1 appropriate to apply to estimates of naphthalene risk obtained by linear extrapolation under a default genotoxic MOA assumption.This procedure is proposed as scientifically credible method to address MOA uncertainty for DMOA carcinogens.3

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An analysis of in vivo hprt mutant frequency in circulating T-lymphocytes in the normal human population: a comparison of four datasets

Cited by 110 publications

References 30 publications

Elevated Expression of Hypoxanthine Guanine Phosphoribosyltransferase within Malignant Tissue

Elevated Expression of Hypoxanthine Guanine Phosphoribosyltransferase within Malignant Tissue

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

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