OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Trimetrexate	52128-35-5	C19-H23-N5-O3
Folate	6484-89-5	C19-H18-N7-O6.Na

ANNOTATED BIBLIOGRAPHY

References updated: 18 April 2016

• Zimmerman HJ. Oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 673-708.

  (Expert review of hepatotoxicity of cancer chemotherapeutic agents published in 1999; trimetrexate is listed as an antineoplastic agent that has not been associated with liver injury).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 549-68.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; trimetrexate is not discussed).
• Chabner BA, Bertino J, Clearly J, Ortiz T, Lane A, Supko JG, Ryan DP. Folic acid analogs. Cytotoxic agents. Chemotherapy of neoplastic diseases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1690-94.

  (Textbook of pharmacology and therapeutics).
• Lin JT, Bertino JR. Trimetrexate: a second generation folate antagonist in clinical trial. J Clin Oncol 1987; 5: 2032-40. [PubMed: 2960788]

  (Review of the chemical structure and mechanism of action of trimetrexate and summary of pilot studies in breast, lung and head and neck cancers, mentions that toxicity is largely myelosuppression, but gastrointestinal, renal and cutaneous adverse events can occur: “transient elevation of liver enzymes has also been reported”).
• Grem JL, Ellenberg SS, King SA, Shoemaker DD. Correlates of severe or life-threatening toxic effects from trimetrexate. J Natl Cancer Inst 1988; 80: 1313-8. [PubMed: 2971817]

  (Analysis of side effects in 272 patients with cancer treated with trimetrexate suggested that leukopenia and mucositis were dose related and that patients with low baseline serum protein levels were more likely to suffer severe side effects; ALT or AST elevations above 5 times ULN occurring in 22% of subjects with serum albumin 3.2 g/dL or below, but only 5-9% with normal values).
• Balis FM, Patel R, Luks E, Doherty KM, Holcenberg JS, Tan C, Reaman GH, et al. Pediatric phase I trial and pharmacokinetic study of trimetrexate. Cancer Res 1987; 47: 4973-6. [PubMed: 2957048]

  (Among 30 children with cancer treated with several doses of trimetrexate, dose limiting toxicities were myelosuppression, mucositis, rash and “mild, dose-related, transient elevations in serum transaminases [2- to 3-fold higher than baseline]”).
• Bertino JR. Trimetrexate: overall clinical results. Semin Oncol 1988; 15 (2 Suppl 2): 50-1. [PubMed: 2966986]

  (Commentary on preliminary studies of trimetrexate in several solid tumors mentions promising results in lung, breast and head and neck cancers; toxicities described as very much like those with methotrexate).
• Allegra CJ, Kovacs JA, Drake JC, Swan JC, Chabner BA, Masur H. Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. J Exp Med 1987; 165: 926-31. [PMC free article: PMC2188293] [PubMed: 2950200]

  (In vitro studies of rat and P. jirovecii dihydrofolate reductase showed superior inhibitory activity of trimetrexate compared to trimethoprim and pyrimethamine and in vivo studies demonstrated its effectiveness in rat P. jirovecii infection).
• Allegra CJ, Chabner BA, Tuazon CU, Ogata-Arakaki D, Baird B, Drake JC, Simmons JT, et al. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med 1987; 317: 978-85. [PubMed: 2958710]

  (Among 49 patients with HIV infection and Pneumocystis jirovecii pneumonia treated with trimetrexate and leucovorin, 63-71% responded including patients who were refractory or intolerant to conventional therapy; side effects were infrequent while ALT or AST elevations above 5 times ULN occurred in 4 [8%] patients, they resolved despite continuing therapy).
• Hughes WT. Pneumocystis carinii pneumonitis. N Engl J Med 1987; 317: 1021-3. [PubMed: 2958709]

  (Editorial on Pneumocystis jirovecii infection in response to article by Allegra [1987: NEJM]).
• Eisenhauer EA, Zee BC, Pater JL, Walsh WR. Trimetrexate: predictors of severe or life-threatening toxic effects. J Natl Cancer Ins. 1988; 80: 1318-22. [PubMed: 2971818]

  (Analysis of 68 patients treated with trimetrexate in cancer chemotherapy trials found that low serum protein levels and metastatic liver disease were predictive of likelihood of severe side effects).
• Trimetrexate for Pneumocystis carinii pneumonia. Med Lett Drugs Ther 1989; 31: 5-6. [PubMed: 2521370]

  (Concise summary of the mechanism of action and efficacy of trimetrexate with leucovorin as therapy of Pneumocystis jirovecii pneumonia shortly after its approval for this use in the US, mentions that when combined with leucovorin, is well tolerated; no mention of ALT elevations).
• Sattler FR, Allegra CJ, Verdegem TD, Akil B, Tuazon CU, Hughlett C, Ogata-Arakaki D, et al. Trimetrexate-leucovorin dosage evaluation study for treatment of Pneumocystis carinii pneumonia. J Infect Dis 1990; 161: 91-6. [PubMed: 2136905]

  (In a dose finding study of trimetrexate and leucovorin in 53 patients with Pneumocystis jirovecii pneumonia, ALT elevations above 5 times ULN occurred in 15 patients [28%] with peak values of 184 to 1205 U/L, but no patients developed jaundice, and all improved despite continuing therapy, none requiring early discontinuation because of liver injury).
• Grem JL, King SA, Costanza ME, Brown TD. Hypersensitivity reactions to trimetrexate. Invest New Drugs 1990; 8: 211-4. [PubMed: 2143501]

  (5 patients had immediate hypersensitivity reactions to infusions of trimetrexate; symptoms included immediate hypotension, loss of consciousness, flushing, fever, and periorbital edema; all resolved with stopping and either corticosteroids or antihistamines or both; no mention of ALT elevations or hepatotoxicity).
• Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. J Antimicrob Chemother 2009; 64: 1282-90. [PMC free article: PMC2775667] [PubMed: 19858161]

  (Among 1122 HIV infected patients with P. jirovecii pneumonia treated at 3 European centers between 1989 and 2004, most were treated with trimethoprim/sulfamethoxazole [81%] or pentamidine [7%] and few with trimetrexate/leucovorin; no discussion of adverse reactions).
• Short CE, Gilleece YC, Fisher MJ, Churchill DR. Trimetrexate and folinic acid: a valuable salvage option for Pneumocystis jirovecii pneumonia. AIDS 2009; 23: 1287-90. [PubMed: 19424049]

  (Among 14 patients with refractory Pneumocystis jirovecii pneumonia treated with trimetrexate and leucovorin, the response rate was 71% and there were no early discontinuations for side effects; no mention of ALT elevations or hepatotoxicity).