Interlaboratory Comparison of Short-Term Carcinogenicity Studies Using CB6F1-rasH2 Transgenic Mice

Takaoka, Masaya; Sehata, Shinya; Maejima, Takanori; Imai, Toshio; Torii, Mikinori; Satoh, Hiroshi; Toyosawa, Kaoru; Tanakamaru, Zen-yo; Adachi, Tamiko; Hisada, Shigeru; Ueda, Makoto; Ogasawara, Hiroyuki; Matsumoto, Masahiro; Kobayashi, Kiyoshi; Mutai, Mamoru; Usui, Tomohiro

doi:10.1080/01926230390183670

Cited by 30 publications

(54 citation statements)

References 15 publications

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“…A recut of the block does not help as the lesion is usually not present in the recut. Similar lesions in Tg.rasH2 mice (Takaoka et al 2003) and in other strains of mice have been diagnosed as acidophilic macrophage pneumonia (Pettan-Brewer and Treuting 2011; Murray and Luz 1990). The incidence of alveolar epithelial hyperplasia parallels the incidence of pulmonary adenomas noted in male and female mice, with hyperplasia generally of lower incidence than adenomas (Paranjpe et al 2013).…”

Section: Discussionmentioning

confidence: 78%

“…This mouse model was endorsed and validated by the International Life Science Institute Health and Environmental Science Institute (ILSI HESI) through an international collaborative project (Robinson and MacDonald 2001) as an alternative to the conventional 2-year carcinogenicity bioassays in mice. Under the ILSI HESI project, 26-week carcinogenicity studies in Tg.rasH2 mice were conducted for 21 compounds at different facilities in the United States, Japan, and Europe (Takaoka et al 2003). These compounds included genotoxic and nongenotoxic human carcinogens, rodent carcinogens/putative human noncarcinogens, and noncarcinogens.…”

Section: Introductionmentioning

confidence: 99%

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Incidence of Spontaneous Non-Neoplastic Lesions in Transgenic CBYB6F1-Tg(HRAS)2Jic Mice

et al. 2013

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Since 2003, the Tg.rasH2 model has been accepted by regulatory agencies worldwide for 26-week short-term carcinogenicity assays as an alternative to the standard 2-year assays in conventional mice. However, over the decade, the number of actual studies conducted with alternative mouse models has remained low. The primary cause for low acceptance of this model has been lack of a historical database for the incidence of spontaneous lesions. Recently, we published the historical control database on spontaneous tumors in the Tg.rasH2 mice. The purpose of this publication is to present a large database pertaining to the non-neoplastic spontaneous lesions noted in Tg.rasH2 mice from studies conducted at our facility. Lesions that are considered unique in Tg.rasH2 mice are skeletal muscle myopathy, vascular anomalies involving various organs, and mesenteric arterial thrombosis. Other notable lesions are extramedullary hematopoiesis of spleen, subacute inflammatory foci in the liver, and infiltration of histiocytes in the lungs.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Incidence of Spontaneous Non-Neoplastic Lesions in Transgenic CBYB6F1-Tg(HRAS)2Jic Mice

et al. 2013

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“…These mice develop spontaneous and chemically induced neoplasms earlier in life and in greater numbers than wild-type mice. The most-common spontaneous neoplasms in control CB6F1-Tg rasH2 mice 8 to 9 months of age are lung adenoma and carcinoma (7.4% incidence), splenic hemangiomas and hemangiosarcomas (5.4%), forestomach squamous cell papillomas and carcinomas (2.4%), and skin neoplasms (1.2%) (21,26).…”

Section: Discussionmentioning

confidence: 99%

“…The incidence of common background findings was compared with controls and published values from different laboratories (26).…”

mentioning

confidence: 99%

Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for Treatment of Hepatitis B

Bridges

Selden

Luo

2008

Antimicrob Agents Chemother

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Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.Telbivudine (␤-L-2Ј-deoxythymidine) is the unmodified ␤-L enantiomer of the naturally occurring nucleoside thymidine (Fig. 1).Its molecular formula is C 10 H 14 N 2 O 5 with a formula weight of 242 g/mol.Nucleoside/nucleotide analogs have been proven to be effective for the treatment of hepatitis B virus (HBV) and human immunodeficiency virus. To date, four nucleoside/nucleotide analogs, lamivudine, adefovir dipivoxil, entecavir, and telbivudine, have been approved by the United States Food and Drug Administration for the treatment of HBV (16,27). These agents vary with respect to antiviral and clinical efficacy, resistance profiles, and tolerability and safety (17). A major safety concern for this class of drugs is mitochondrial toxicity, which is manifested as hepatic failure, nephrotoxicity, pancreatitis, neuropathy, myopathy, and lactic acidosis (1,2,3,5,6,8,15,18,19,22,24,29). Furthermore, emergence of drug-resistant viruses in patients undergoing long-term maintenance therapy with these drugs can result in diminished drug efficacies (9, 30).Telbivudine shows potent, selective, and specific antiviral activity against HBV and other hepadnaviruses (4, 14). Telbivudine is phosphorylated by intracellular thymidine kinases to the active triphosphate form, which has an intracellular halflife of 14 h (12, 25). Telbivudine 5Ј-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, dTTP. Incorporation of telbivudine 5Ј-triphosphate into v...

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“…It is important that each facility conducting these studies use their data to determine this list, ensuring that Keenan et al 2009;Takaoka et al 2003). In creating a select tissue list for low-and mid-dose groups in 26-week Tg.rasH2 mouse studies, we took into consideration (a) common tumors, (b) uncommon tumors seen grossly, (c) uncommon tumors not seen grossly, (d) organ weight variations with accountable microscopic lesions, and (e) target organs identified in the high-dose groups.…”

Section: Discussionmentioning

confidence: 99%

The 26-Week Tg.Rash2 Mice Carcinogenicity Studies

2013

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A typical 26-week Tg.rasH2 mouse carcinogenicity study usually has 4 dose groups, composed of 25 mice/sex, which include 1 control and 3 test article-treated groups. In every study, there is a protocol required full tissue list of 49 tissues which is examined microscopically in all animals of these 4 dose groups. Based on retrospective analysis of the historical control data collected from studies conducted in Tg.rasH2 mice from 2004 to 2012, we propose that a full tissue list be examined as usual in the control and high-dose groups; however, in the low-and mid-dose groups, only select tissues should be examined. The select tissue list is generated after analyzing common tumors, uncommon tumors seen grossly, uncommon tumors not seen grossly, organ weight variations with accountable microscopic lesions, and target organs identified in the high-dose groups. The proposed changes to the International Conference on Harmonization S1 guidance may lead to an increased need for 26-week Tg.rasH2 mice studies. The time savings resulting from processing and evaluating a select tissue list rather than a full tissue list from low-and mid-dose groups of Tg.rasH2 mouse studies will further accelerate early completion of these studies without compromising the quality and integrity.

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Interlaboratory Comparison of Short-Term Carcinogenicity Studies Using CB6F1-rasH2 Transgenic Mice

Cited by 30 publications

References 15 publications

Incidence of Spontaneous Non-Neoplastic Lesions in Transgenic CBYB6F1-Tg(HRAS)2Jic Mice

Incidence of Spontaneous Non-Neoplastic Lesions in Transgenic CBYB6F1-Tg(HRAS)2Jic Mice

Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for Treatment of Hepatitis B

The 26-Week Tg.Rash2 Mice Carcinogenicity Studies

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