Spontaneous tumors in control F344 and Charles River-CD rats and Charles River CD-1 and B6C3HF1 mice

Sher, Sanford P.; Jensen, R; Bokelman, Delwin L.

doi:10.1016/0378-4274(82)90113-8

Cited by 78 publications

(13 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The focal interstitial fibrosis of lungs seen in this study is consistent with the diffuse pulmonary alveolar damage and granulomatous pulmonary interstitial reaction (44, 49) reported in man following methotrexate treatment.. In this rat bioassay, methotrexate did not increase the overall tumor incidence or multiplicity of tumors when compared to either concurrent or published historical controls (42). Furthermore, the diversity and incidence of tumor types were generally low when compared to the historical control.…”

Section: Discussionsupporting

confidence: 89%

Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Hall¹,

Tnham²,

Manandhar³

et al. 1988

Toxicol Pathol

View full text Add to dashboard Cite

ABSTRAC~The genotoxic and oncogenic potentials of methotrexate were studied in Sprague-Dawley rats. The rats received 0.1, 0.2, or 0.4 mg/kg of methotrexate as dietary admixtures on a 5 days on, 9 days 0% regimen for 23 months. In the females of the high-dose group, there was a significant increase in mortality starting at 18 months. Significant increases in the number of rats with focal pulmonary interstitial fibrosis were seen in both sexes at the high-dose level. At the mid-and high-dose levels of both sexes, there was a significantly increased number of rats with myeloid and erythroid bone marrow hypoplasia. There was no evidence of either early onset or increased incidence ofany tumor type in the treatment groups. Therefore, it is concluded that methotrexate does not have oncogenic potential. Also, at terminal sacrifice, bone marrow cells were harvested from selected animals on the last day of the 5-day dosing cycle and cytogenetic evaluation was performed. No significant increase in chromosomal aberrations was seen in any dose group relative to the control group. This observation further substantiates the absence of oncogenic potential due to methotrexate in rats. INTRODUC~IONMethotrexate is an antimetabolite which acts as a folic acid antagonist (1 1). It is one of the few drugs whose mechanism of action has been extensively studied and well characterized. Methotrexate, also known as amethopterin, is a potent inhibitor of dihydrofolate reductase which converts dihydrofolate to tetrahydrofolate. Tetrahydrofolate and subsequent folic acid derivatives serve as cofactors in the transfer of single carbon atoms in the synthesis of purines and thymidylic acid required for DNA synthesis.Methotrexate has been recognized for many years as one ofthe most effective chemotherapeutic agents for certain leukemias, choriocarcinoma and Burkitt's lymphoma as well as other neoplastic diseases (22). More recently, it has been successfully used for the treatment of severe recalcitrant psoriasis (3, 10) and rheumatoid arthritis (5) for durations longer than normally used in patients with cancer. In order to determine the oncogenic potential or the genetic liability of methotrexate, a 2-year lifetime bioassay in rats was performed. This paper describes the results of the carcinogenicity study as well as chromosomal analysis from rats in the lifetime bioassay. Furthermore, we have reviewed the Iiterature on the carcinogenic, co-carcinogenic and mutagenic potentials of methotrexate. Based on all these studies, an overall safety of methotrexate has been assessed. METHODS ClieniicalMethotrexateO,' N-[4-[[(2,4-diamino-6-pteridinyl)methylJmethylamino]benzoyIJ-l-glutamic acid (Fig. 1) is a bright yellow-orange, odorless, crystalline powder with a molecular weight of 454.5. AnimalsSprague-Dawley rats were obtained from Charles River Breeding Laboratories. The rats weighing approximately 75 g at the start of the study were assigned to different groups using a table ofrandorn numbers. All animals were individually identified by a system ...

show abstract

Section: Discussionsupporting

confidence: 89%

Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Hall¹,

Tnham²,

Manandhar³

et al. 1988

Toxicol Pathol

View full text Add to dashboard Cite

show abstract

“…Although there are numerous reports on naturally occurring microscopic lesions [1,3,[5][6][7][8][9][10][11][12][13][14][15][16], there is a paucity of information on gross necro -psy findings in these strains of rodents . The purpose of this investigation was to establish a historical control data base of the organ weight and naturally occurring gross morphologic alterations which were observed in toxicological studies with F344 rats and B6C3F1 mice.…”

mentioning

confidence: 99%

Historical Control Data of Organ Weight and Gross Findings in F344/DuCrj Rats and B6C3F<SUB>1</SUB> Mice

Iwata¹,

Hagiwara²,

Katoh³

et al. 1993

Experimental Animals

View full text Add to dashboard Cite

“…However, in autopsy series of elderly females the prevalence is 1,000-fold greater, emphasizing that most prolactinomas are clinically silent and common in the elderly population (6). Prolactinomas are also a common cause of death in female aged rats of a number of strains (7)(8)(9). Treatment of prolactinomas with dopamine agonists reduces pituitary prolactin expression and reverses lactotroph hyperplasia, emphasizing the link between prolactin expression and cellular proliferation.…”

mentioning

confidence: 99%

Galanin regulates prolactin release and lactotroph proliferation

Wynick

Small

Bacon

et al. 1998

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

187

138

View full text Add to dashboard Cite

The neuropeptide galanin is predominantly expressed by the lactotrophs (the prolactin secreting cell type) in the rodent anterior pituitary and in the median eminence and paraventricular nucleus of the hypothalamus. Prolactin and galanin colocalize in the same secretory granule, the expression of both proteins is extremely sensitive to the estrogen status of the animal. The administration of estradiol-17␤ induces pituitary hyperplasia followed by adenoma formation and causes a 3,000-fold increase in the galanin mRNA content of the lactotroph. To further study the role of galanin in prolactin release and lactotroph growth we now report the generation of mice carrying a loss-of-function mutation of the endogenous galanin gene. There is no evidence of embryonic lethality and the mutant mice grow normally. The specific endocrine abnormalities identified to date, relate to the expression of prolactin. Pituitary prolactin message levels and protein content of adult female mutant mice are reduced by 30-40% compared with wild-type controls. Mutant females fail to lactate and pups die of starvation͞dehydration unless fostered onto wild-type mothers. Prolactin secretion in mutant females is markedly reduced at 7 days postpartum compared with wild-type controls with an associated failure in mammary gland maturation. There is an almost complete abrogation of the proliferative response of the lactotroph to high doses of estrogen, with a failure to up-regulate prolactin release, STAT5 expression or to increase pituitary cell number. These data further support the hypothesis that galanin acts as a paracrine regulator of prolactin expression and as a growth factor to the lactotroph.The factors that regulate proliferation of the lactotroph are largely unknown. Further, the relationship of altered prolactin secretion to lactotroph proliferation is also unclear. Pregnancy induces a coordinated increase in prolactin release and the number of lactotrophs, with a marked involution in their number once lactation ceases (1-4). In contrast, a sustained and uncontrolled proliferation of lactotrophs culminates in the development of prolactin-secreting adenomas (prolactinomas) resulting in inappropriate lactation. The prevalence of prolactinomas is an estimated 100 per million (5). However, in autopsy series of elderly females the prevalence is 1,000-fold greater, emphasizing that most prolactinomas are clinically silent and common in the elderly population (6). Prolactinomas are also a common cause of death in female aged rats of a number of strains (7-9). Treatment of prolactinomas with dopamine agonists reduces pituitary prolactin expression and reverses lactotroph hyperplasia, emphasizing the link between prolactin expression and cellular proliferation. Prolactinomas arise as monoclonal neoplasms, indicating that one or more somatic mutations underlie tumor pathogenesis. A large and increasing body of literature has failed to identify mutations in known protooncogenes in human prolactinomas (10-12). In contrast, exogenous estro...

show abstract

Spontaneous tumors in control F344 and Charles River-CD rats and Charles River CD-1 and B6C3HF1 mice

Cited by 78 publications

References 5 publications

Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Historical Control Data of Organ Weight and Gross Findings in F344/DuCrj Rats and B6C3F<SUB>1</SUB> Mice

Galanin regulates prolactin release and lactotroph proliferation

Contact Info

Product

Resources

About