METHOTREXATE, (R)- (D-methotrexate) as a contaminant of commercial methotrexate, a chemotherapy agent and immune system suppressant. Methotrexate from various commercial sources has been found to contain 0.5 to 48% (w/w) of the enantiomer D-methotrexate. D-Methotrexate was found to be a good inhibitor of dihydrofolate reductase from both murine and human tumor cells, but was a poor inhibitor of L1210 and CCRF-CEM cell growth. In animal experiments with dogs and mice, D-methotrexate was rapidly absorbed from the intestine and excreted by the kidneys.

Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Aminopterin is a synthetic derivative of pterins with antineoplastic and immunosuppressive properties. As a folate analog, aminopterin competes for the folate binding site of the enzyme dihydrofolate reductase, thereby blocking tetrahydrofolate synthesis, and resulting in depletion of nucleotide precursors and inhibition of DNA, RNA and protein synthesis. Aminopterin was marketed by Lederle Laboratories (Pearl River, New York) in the United States from 1953 to 1964 for the indication of pediatric leukemia. The closely related antifolate methotrexate was simultaneously marketed by the company during the same period. Aminopterin was discontinued by Lederle Laboratories in favor of methotrexate due to manufacturing difficulties of the former. During the period Aminopterin was marketed, the agent was used off-label to safely treat over 4,000 patients with psoriasis in the United States, producing dramatic clearing of lesions. The use of aminopterin in cancer treatment was supplanted in the 1950s by methotrexate due to the latter's better therapeutic index in a rodent tumor model. Now in a more pure preparation and supported by laboratory evidence of superior tumor cell uptake in vitro, aminopterin is being investigated in clinical trials in leukemia as a potentially superior antifolate to methotrexate.

Cycloguanil is a dihydrofolate reductase inhibitor and is a metabolite of the antimalarial drug proguanil. The parent drug proguanil was suggested to contribute to the antimalarial activity as well, but the mechanism of action is unknown. Proguanil is a prodrug that is metabolized to its main active metabolite, cycloguanil, mostly via CYP2C19. There is significant variation in proguanil pharmacokinetics.12 CYP2C19 is the predominant enzyme catalyzing the bioactivation of proguanil to cycloguanil. Cycloguanil is one of the few antimalarial drugs that act on both the erythrocytic and on the pre-erythrocytic (hepatic) forms of the malaria parasites. Although cycloguanil is not currently in general use as an antimalarial, the continuing development of resistance to current antimalarial drugs has led to renewed interest in studying the use of cycloguanil in combination with other drugs.

Cycloguanil is a dihydrofolate reductase inhibitor and is a metabolite of the antimalarial drug proguanil. The parent drug proguanil was suggested to contribute to the antimalarial activity as well, but the mechanism of action is unknown. Proguanil is a prodrug that is metabolized to its main active metabolite, cycloguanil, mostly via CYP2C19. There is significant variation in proguanil pharmacokinetics.12 CYP2C19 is the predominant enzyme catalyzing the bioactivation of proguanil to cycloguanil. Cycloguanil is one of the few antimalarial drugs that act on both the erythrocytic and on the pre-erythrocytic (hepatic) forms of the malaria parasites. Although cycloguanil is not currently in general use as an antimalarial, the continuing development of resistance to current antimalarial drugs has led to renewed interest in studying the use of cycloguanil in combination with other drugs.

Cycloguanil is a dihydrofolate reductase inhibitor and is a metabolite of the antimalarial drug proguanil. The parent drug proguanil was suggested to contribute to the antimalarial activity as well, but the mechanism of action is unknown. Proguanil is a prodrug that is metabolized to its main active metabolite, cycloguanil, mostly via CYP2C19. There is significant variation in proguanil pharmacokinetics.12 CYP2C19 is the predominant enzyme catalyzing the bioactivation of proguanil to cycloguanil. Cycloguanil is one of the few antimalarial drugs that act on both the erythrocytic and on the pre-erythrocytic (hepatic) forms of the malaria parasites. Although cycloguanil is not currently in general use as an antimalarial, the continuing development of resistance to current antimalarial drugs has led to renewed interest in studying the use of cycloguanil in combination with other drugs.