Ns Ch3

20 Raltitrexed (RTX)



Like MTX, RTX utilizes the RFC and is an excellent substrate for FPGS, and much of its activity arises from its polyglutamates. Unlike MTX however, RTX is a relatively weak inhibitor of DHFR, instead exerting its efficacy through inhibition of TS. Because the polyglutamates are retained within cells for prolonged periods, RTX has a convenient dosing regimen of once every 3 weeks. As with other drugs dependent on the RFC and or FPGS, mutations or reduced expression of these proteins leads to resistance to RTX.87 Trimetrexate

Trimetrexate (21, TMTX) is a nonclassical type A lipophilic DHFR inhibitor. Unlike MTX and RTX, TMTX does not utilize the RFC and cannot be polyglutamated. Thus, from the standpoint of RFC or FPGS related resistance, TMTX should have some advantage. A substituent at the C5 position of the quinazoline ring lends improved activity to the scaffold. Chloro or methyl substituents are an order of magnitude more potent against L1210 leukemia cells than the C5-H analogs.88 TMTX has been launched for the treatment of pneumocystis carinii infections as well as neoplasms in many countries. The TMTX/LV combination is both effective and nontoxic in the treatment of pneumocystis carinii, as

LV cannot rescue this organism due to the lack of a LV transporter, while normal host cells are protected by LV With LV TMTX has also shown promise in combination therapy. In particular, the combination of TMTX, 5FU, and LV has shown a 20% response in previously treated gastrointestinal cancer and a 50% response in previously untreated patients with colorectal cancer.89 Further it has been shown that leukemic cells resistant to MTX due to aberrant transport mechanisms are sensitive to TMTX.90 Antifolates in clinical trials

Pralatrexate (22, PDX) is a classical DHFR inhibitor, currently in phase II single agent trials against NSCLC. Phase I trials in combination with docetaxel for the same indication are also under way. A new phase I trial started in 2005 in combination with vitamin B12 and folic acid also in NSCLC. Synthesis of PDX was based on previous observations that 10-N-propargyl-5,8-dideazafolic acid showed excellent TS inhibition. Replacement of the 10-nitrogen group in the typical para-aminobenzoic acid side chain with a carbon resulted in PDX, which showed a 10-fold advantage over MTX in L1210 cells.91 The primary side effect of PDX in phase II trials with previously treated NSCLC patients was stomatitis with no significant myelosuppression observed. Of the 38 evaluable patients, four had major objective responses and 12 had stable disease. Reverse transcription-PCR was performed to measure the relative expression of FPGS and RFC-1 in patients, with the data showing no trend with respect to FPGS. The polymerase chain reaction (PCR) data did suggest that tumors expressing high levels of RFC might be more sensitive to PDX.92

Pelitrexol (23, PTO) is a GARFT inhibitor currently in phase I clinical trials. A closely related analog, AG-2034 (31), is a classical antifolate showing affinity for FPGS. Glutamation (glu-5) results in a 28-fold increase in affinity for GARFT.93 Mid -stage development was reported in June 2003.94



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