Toxicity of MTX

There is an increased risk of toxicity of MTX when administered with the NSAIDs, salicylates, oral antidiabetic drugs, phenytoin, tetracycline, and probenecid. There is an additive bone marrow depressant effect when administered with other drug known to depress the bone marrow or with radiation therapy. There is an increased risk for nephrotoxicity when MTX is administered with other drug that cause nephrotoxicity. When penicillamine is administered with digoxin, decreased blood levels of digoxin may occur. There is a decreased absorption of penicillamine when the dmg is administered with food, iron preparations, and antacids. 

On the surface, it would appear that a drug which could not form polyglutamates and therefore not be well retained by cells would be an inappropriate candidate for an antitumor drug. However, in common with all cancer chemotherapeutic agents, the dose-limiting toxicity of MTX is associated with non-tumor tissue (e.g., liver, marrow, etc.) and the highly retentive polyglutamate forms... 

Mucosal lesions (Fig. 1), nausea, and diarrhea are also consequences of MTX therapy. At doses of 15 to 25 mg used for arthritis, nausea has been reported by 40% to 60% of patients and diarrhea over 10% of the time (94,95). Stomatitis had also been reported in over 10% of cases from another series (96). This appears to be dose related, with no difference between placebos for any of these effects in a randomized trial of MTX for sarcoidosis (35). However, in a larger series of sarcoidosis, some sarcoidosis patients did discontinue MTX because of nausea (8,97). The hematologic and G1 toxicity of MTX can be minimized by the use of low-dose folic acid supplement (1-mg folic acid per day) (98) without affecting the efficacy of MTX. MTX leads to decreased homocysteine levels that can be reversed with folic acid supplementation (99). 

Figure 7. Toxicity of poly-L-lysine (9), MTX(poly-L-lysine) poly-o-lysine f OX MTXipoly-Thlyane) to rat hepatocytes in culture.

Experiments which examine the comparative toxicities of the poly-L- and -D- carriers for hepatocytes and hepatomas indicate a low level of toxicity with the hepatoma. However, an elevated toxic effect is observed for the hepatocyte with the D-isomeric carrier. When the drug is bound to the carrier little alteration is observed in the toxic response of the hepatocyte suggesting that in its resting state it has little requirement for dihydrofolate reductase. The results shown in Table 111 illustrate this point more clearly where only 26Z of reductase activity remains after treating the hepatocytes with 2 micromolar MTX(poly-L-lyaine) yet 752 cellular viability resiains. This contrasts with the response of the hepatoma cell line (Table IV), where both dihydrofolate reductase and 90Z cell growth of both transport defective and non-defective cell lines is eliminated by treatment with 2.8 micromolar MTX(poly-L-lysine). 

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