Methotrexate: Assessment of In Vivo Clastogenicity and Carcinogenicity

Abstract

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 ...

Uncertainty and variability in human exposure limits – A chemical-specific approach with ciprofloxacin and methotrexate

“…We therefore decided to use toxicity data from experimental animal studies as a starting point. Chronic carcinogenicity studies have not reported significant effects after either methotrexate (Hall et al 1988;IARC 1987) or ciprofloxacin exposure (US FDA 2013). Instead, a 28-d study on myelosuppression in mice (Ohbayashi et al 2010) and a 7-d study on chondrotoxicity in rats (Li et al 2004) were selected for methotrexate and ciprofloxacin, respectively.…”