Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimetrexate glucuronate, a dihydrofolate reductase inhibitor related to methotrexate, was developed by Parke-Davis as an alternative antineoplastic agent for tumors, especially sarcomas, that had developed resistance to methotrexate. This is a report on a patient with AIDS who developed Pneumocystis carinii pneumonia, which was treated with trimethoprim sulfamethoxazole (Bactrim) with poor response, then with pentamidine with poor response, and finally with trimetrexate glucuronate (Neutrexin) and leucovorin rescue, with good response. The patient also suffered from cutaneous and visceral Kaposi's sarcoma (KS), which had been treated with high- dose HCG1 and well recognized chemotherapeutic protocols. Both HCG and chemotherapy resulted in tumor regression. The patient's KS flared, however, when he developed pneumocystis pneumonia. When trimetrexate glucuronate and leucovorin rescue were administered, his tumor burden decreased significantly, suggesting that trimetrexate glucuronate may have some activity against KS. The regression of KS in this anecdotal observation may be secondary to a delayed response from HCG and/or chemotherapy, or secondary to a spontaneous partial regression. Such regression may only be of the decreased edema around the KS lesions and not the neoplastic tissue itself. If other clinicians see this same phenomenon, however, it is possible that trimetrexate glucuronate may have an anti-KS effect. Such future clinical observations would warrant further testing at the basic science level.
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PMID:Trimetrexate glucuronate associated with anti-Kaposi sarcoma effect. 1136 14

Six previously undescribed N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepines with water-solubilizing O-carboxyalkyloxy or O-carboxybenzyloxy side chains at the 2'-position were synthesized and compared with trimethoprim (TMP) and piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic organisms known to cause significant morbidity and mortality in patients with AIDS and other disorders of the immune system. The ability of the new analogues to inhibit reduction of dihydrofolate to tetrahydrofolate by Pc, Tg, Ma, and rat DHFR was determined, and the selectivity index (SI) was calculated from the ratio IC(50)(rat DHFR)/IC(50)(Pc, Tg, or Ma DHFR). The IC(50) values of the 2'-O-carboxypropyl analogue (10), with SI values in parentheses, were 1.1 nM (1300) against Pc DHFR, 9.9 nM (120) against Tg DHFR, and 2.0 nM (600) against Ma DHFR. The corresponding values for the 2'-O-(4-carboxybenzyloxy) analogue (12) were 1.0 nM (560), 22 nM (21), and 0.75 nM (630). By comparison, the IC(50) and SI values for TMP were Pc, 13 000 nM (14); Tg, 2800 nM (65); and Ma, 300 nM (610). For the prototypical potent but nonselective inhibitors PTX and TMX, respectively, these values were Pc, 13 nM (0.26) and 47 nM (0.17); Tg, 4.3 nM (0.76) and 16 nM (0.50); Ma, 0.61 nM (5.4) and 1.5 nM (5.3). Thus 10 and 12 met the criterion for DHFR inhibitors that combine the high selectivity of TMP with the high potency of PTX and TMX.
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PMID:Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. 1511 91