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34 ICI198583 26 Plevitrexed (PTX)

PTX is currently in phase I/II clinical trials for the treatment of gastric and other solid tumors. A previous phase II/III trial in metastatic pancreatic cancer was terminated due to the severity of adverse events. Phase II data for patients with recurrent NSCLC has been reported, and showed 43% achieving stable disease following a 3 week cycle of treatment on days 1 and 8.101

MDAM (27) is a nonpolyglutamatable type B nonclassical antifolate DHFR inhibitor. The gamma-methylene group completely blocks polyglutamation via FPGS, but MDAM does not inhibit the action of FPGS. MDAM is currently in phase I clinical trials in patients with advanced solid tumors. Of 17 evaluable patients in the study, three demonstrated stable disease. No complete or partial responses were observed. MDAM is a DHFR inhibitor, with superior activity relative to MTX in rodent models, perhaps partially due to a combination of enhanced transport to tumor cells and slower deactivation by aldehyde oxidase.104

PT-523 (28) is a nonpolyglutamatable type B nonclassical antifolate currently in phase I clinical trials. It has been shown to be a potent inhibitor of DHFR, and efficiently utilizes the RFC for cellular influx.105 PT-523 was designed as an analog of APA-L-ORN, which was shown to be a potent inhibitor of DHFR and FPGS, but had poor cellular activity. It was felt that inhibition of DHFR and FPGS could lead to more efficacious compounds and an effort ensued to attach potentially labile groups to the terminal NH2 of APA-L-ORN that may deliver the agent more efficiently into cells.106

PT-523 came out of this effort as a very potent DHFR inhibitor with cell growth inhibition substantially greater than MTX. However, detailed mechanistic studies reveal that this increased activity is not due to cleavage to APA-L-ORN and inhibition of FPGS.107 PT-523 is currently in phase I/II trials in NSCLC, as well as phase I trials in patients with advanced solid tumors who had failed curative or survival-prolonging therapy.

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