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Methotrexate

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General Features                  Clinical Study                  Chemical Intervention                 Pharmacological Aspects                 
Radiobiological Aspects                  Biological Models                  Biological Target                  Toxicity                 


TOXICITY

Toxicity
values:
IC10 of methotreaxate in human breast cancer MDA-MB-231 cell when treated for 24 hrs ranged between 0.01 and 12 mmol/L [1]
Adverse
reactions:
Effect on
various
metabolisms/
pathways:
Mutagenicity
or Carcinogen-
icity Data:
Methotrexate was found to be non-mutagenic in Salmonella/microsome test.[2]
Sprague-Dawley rats receiving 0.1, 0.2, or 0.4 mg/kg of methotrexate as dietary admixtures on a 5 days on, 9 days off, regimen for 23 months, did not show ny clastogenicity and oncogenic potential.[3]
Fertility: methotrexate (at the dose of 20 mg/kg once)induced sperm head abnormalities, seminiferous tubule damage, sperm DNA damage, TUNEL positive cells and increased sperm counts in mice.[4]
Methotrexate treatment had no unfavourable effects on fertility of psoriatic male patients.[8]
Pregnancy: Methotrexate is given to ICR mice on day 10 (stage 18) of gestation. No malformations were produced at doses shown to be embryotoxic in humans, rats, rhesus monkeys, and rabbits (0.3–10 mg/kg), although a significant increase in resorption rate was observed in litters treated with 10 mg/kg. Doses between the LD10 and the LD50 (25 and 50 mg/kg) produced a parallel increase in intrauterine death and congenital defects.[5]
Methotrexate was found highly embryotoxic in postimplantation rat embryos; 0.3 mg/kg ip or less caused nearly total embryolethality with slight teratogenicity. When rabbit embryos were given 19.2 mg/kg iv during days 10 to 15 of gestation, produced little death and a constant spectrum of malformation in a high percentage of offspring. Cleft palate, skull defects, and severe fore- and hindlimb dysplasias, occurred with a high degree of regularity and were strongly dose and developmental-stage specific.[6]
Breast Feeding: After oral administration to a lactating patient with choriocarcinoma, methotrexate was found to be excreted in milk at low but readily detectable levels.[7]
REFERENCES
1. Costantini DL et al, Methotrexate, Paclitaxel, and Doxorubicin radiosensitize HER2-Amplified human breast cancer cells to the Auger electron–emitting radiotherapeutic agent 111In-NLS-Trastuzumab. J Nucl Med 2010; 51:477–483.
http://dx.doi.org/10.2967/jnumed.109.069716
2. Benedict WF et al, Mutagenicity of cancer chemotherapeutic agents in the Salmonella/microsome test. Cancer Res. 1977 ;37(7 Pt 1):2209-13.
http://cancerres.aacrjournals.org/content/37/7_Part_1/2209.long
3. Hall C et al, Methotrexate: assessment of in vivo clastogenicity and carcinogenicity. Toxicologic Pathology 1988;16(1):10-21.
http://dx.doi.org/10.1177/019262338801600102
4. Padmanabhan S et al, Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: Intervention of folic and folinic acid. Mutat Res 2009; 673(1): 43–52.
http://dx.doi.org/10.1016/j.mrgentox.2008.11.011
5. Skalko RG, Gold MP, Teratogenicity of methotrexate in mice. Teratology. 1974;9(2):159-63.
http://dx.doi.org/10.1002/tera.1420090206
6. Jordan RL, Wilson JG, Schumacher HJ, Embryotoxicity of the folate antagonist methotrexate in rats and rabbits. Teratology. 1977;15(1):73-9.
http://dx.doi.org/10.1002/tera.1420150110
7. Johns DG et al, Secretion of methotrexate into human milk. Am J Obstet Gynecol. 1972;112(7):978-80.
http://dx.doi.org/10.1016/0002-9378(72)90824-1
8. El-Beheiry A et al, Methotrexate and fertility in men. Arch Andrology 1979;3(2):177-9.
http://dx.doi.org/10.3109/01485017908985067