Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
CURRENT STATUS OF TRIMETREXATE, A FOLATE ANTAGONIST WITH ANTINEOPLASTIC AND ANTIPROTOZOAL PROPERTIES
Cancer Treat Res; 42:79-95 1989. Unique Identifier : AIDSLINE ICDB/90656918 Lin JT; Bertino JR; Program of Developmental Therapy and Clinical Investigation,; Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York,; NY 10021
Abstract:
Trimetrexate (5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]-2,4-quinazoli- nediamine) is a 2,4-diaminoquinazoline folate analog originally synthesized as an antimalarial agent. Preclinical and clinical data on this agent are summarized. Trimetrexate differs from methotrexate (MTX) in its transport and intracellular retention. Toxicity has been tolerable, primarily hematologic, with rapid recovery. Nonhematologic toxicity includes rash, mucositis, nausea and vomiting, and elevation of values of renal and liver function tests. Although preclinical tests suggested possible toxicity from inhibition of histamine-metabolizing enzymes, the expected side effects such as headache, wheezing, and urticarial rash have either been reported rarely or not at all, suggesting that this may not be a significant mode of toxicity. CNS toxicity has not been reported, despite preclinical data of seizures in mice given rapid iv bolus infusion. Nevertheless, these preclinical data suggest caution in the use of equivalently large doses (300-450 mg/m2) or in possible future trials of intrathecal administration. Results of Phase II trials indicate that trimetrexate has activity against breast, non-small cell lung, and head and neck tumors. Additional trials are in progress to evaluate this drug alone or in combination with other drugs in other neoplasms. Trimetrexate also is effective against Pneumocystis carinii pneumonia in AIDS patients when combined with leucovorin rescue, and is active in vitro and in vivo against Toxoplasma gondii. Trimetrexate may be especially useful against tumors resistant to MTX because of impaired transport. Since such a defect would also affect transport of reduced folates, selective toxicity against resistant cells might be achieved by the use of high doses of trimetrexate combined with leucovorin to rescue host cells preferentially. Transport-resistant cells also require higher levels of reduced folates to survive. Thus, the combination of trimetrexate with a folate-depleting enzyme, carboxypeptidase G2, has been suggested as a means of achieving selective antitumor toxicity. (86 Refs)
Keywords: Acquired Immunodeficiency Syndrome/COMPLICATIONS Animal Antineoplastic Agents/*THERAPEUTIC USE Antiprotozoal Agents/*THERAPEUTIC USE Chemistry Clinical Trials Drug Evaluation Drug Resistance Folic Acid Antagonists/*THERAPEUTIC USE Human Neoplasms/*DRUG THERAPY Pneumonia, Pneumocystis carinii/DRUG THERAPY Quinazolines/PHARMACOKINETICS/*THERAPEUTIC USE Tetrahydrofolate Dehydrogenase/ANTAGONISTS & INHIB Tumor Cells, Cultured/*DRUG EFFECTS CLINICAL TRIAL JOURNAL ARTICLE REVIEW REVIEW, TUTORIAL 900130
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Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
