Chronic toxicity of methotrexate in mice

J Natl Cancer Inst. 1977 Mar;58(3):735-41. doi: 10.1093/jnci/58.3.735.

Abstract

Daily (five times/week) administration of 0.25-2 mg methotrexate (MTX)/kg to 5- to 6-week-old male C57BL/6, DBA/2, and C3H mice for 12-18 months was well tolerated, apart from minimal cellular suppression in the lymphoid tissues, testes, and skin. Larger doses of MTX (3-6 mg/kg) given to 5- to 6-week-old mice produced well-known acute to subacute hematopoietic and gastrointestinal damage that leads to early death. These young mice did not develop other lesions that were described in humans after long-term MTX administration, nor was the toxicity cumulative. A large difference was observed in the ability of mice of different ages to withstand the toxic effects of MTX; 16-week-old mice were able to survive daily doses of 3-6 mg/kg up to 18 months. Histologic studies of these mice showed a more pronounced cellular depression of the lymphoid tissues, testes, and skin. Osteoporosis was also observed in these older mice that tolerated the drug for 10 months or longer, thus providing a laboratory animal model for further study of this MTX-induced lesion.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Bone Marrow / drug effects
  • Bone and Bones / pathology
  • Digestive System / drug effects
  • Drug Administration Schedule
  • Female
  • Infertility, Male / chemically induced
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / toxicity*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Osteoporosis / chemically induced
  • Pregnancy
  • Skin / drug effects
  • Skin / pathology
  • Species Specificity
  • Spleen / drug effects
  • Testis / drug effects
  • Testis / pathology

Substances

  • Methotrexate