Life-span carcinogenicity tests with 4-amino-N10-methylpteroylglutamic acid (methotrexate) in Swiss mice and Syrian golden hamsters

Rustia, Mario; Shubik, Philippe

doi:10.1016/0041-008x(73)90269-x

Cited by 40 publications

(13 citation statements)

References 22 publications

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“…Acute toxicity of methotrexate was measured in numerous studies, starting in 1950 with measurements in mice, rats, and dogs (Ferguson et al, 1950; Philips et al, 1950). Only later, in the 1970s, rodents were subjected to low-dose, long-term treatment with methotrexate to measure its toxicity (Freeman-Narrod and Narrod, 1977; Rustia and Shubik, 1973). Methotrexate given to 7-week-old Syrian hamsters for several months was tolerated well at 5, 10, and 20ppm (Rustia and Shubik, 1973).…”

Section: Resultsmentioning

confidence: 99%

“…No data or outliers were excluded from any analysis. (Rustia and Shubik, 1973). Survival probability is on the y-axis, and time (in weeks) is on the x-axis.…”

Section: Discussionmentioning

confidence: 99%

“…Methotrexate given to 7-week-old Syrian hamsters for several months was tolerated well at 5, 10, and 20ppm (Rustia and Shubik, 1973). Methotrexate was also tolerated quite well in mice when administered at 3, 5, 8, or 10ppm in the diet (Rustia and Shubik, 1973) or by IP injection at 0.25-2mg/kg (Freeman-Narrod and Narrod, 1977). We reasoned that those long-term studies might offer helpful information about the role of folate limitation in longevity in mice.…”

Section: Inhibitors Of 1c Metabolic Enzymes Extend the Lifespan Of Ye...mentioning

confidence: 99%

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Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice

Blank,

Hammer,

Boatright

et al. 2024

Preprint

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Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual’s age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

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Section: Resultsmentioning

confidence: 99%

“…No data or outliers were excluded from any analysis. (Rustia and Shubik, 1973). Survival probability is on the y-axis, and time (in weeks) is on the x-axis.…”

Section: Discussionmentioning

confidence: 99%

Section: Inhibitors Of 1c Metabolic Enzymes Extend the Lifespan Of Ye...mentioning

confidence: 99%

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Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice

Blank,

Hammer,

Boatright

et al. 2024

Preprint

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“…duration and larger number ofanimals did not demonstrate an increased incidence of lung tumors (37,48). In addition, methotrexate has been administered in combination with known carcinogens (Table VII) to test for its co-carcinogenic potential.…”

Section: Discussionmentioning

confidence: 99%

Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Hall¹,

Tnham²,

Manandhar³

et al. 1988

Toxicol Pathol

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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 ...

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“…Postoperatively I give papaveretum 10-20 mg intramuscularly as soon as full consciousness returns but before severe pain is felt. 3 SIR,-Too much narcotic analgesic, like too little gruel, is not a good thing. The opportunity to ask for less would have been of benefit to the group of patients given continuous papaveretum infusions by Dr J A Catling and others (16 August, p 478).…”

Section: Barry Lewismentioning

confidence: 99%

Comparison of continuous and intermittent papaveretum after cholecystectomy.

1980

BMJ

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Life-span carcinogenicity tests with 4-amino-N10-methylpteroylglutamic acid (methotrexate) in Swiss mice and Syrian golden hamsters

Cited by 40 publications

References 22 publications

Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice

Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice

Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Comparison of continuous and intermittent papaveretum after cholecystectomy.

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