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American Journal of Clinical Oncology Dec 1995A Phase II trial was conducted in patients with metastatic malignant melanoma with DTIC 250 mg/m2 intravenously for 5 days alternating monthly with Piritrexim (PTX)... (Clinical Trial)
Clinical Trial
A Phase II trial was conducted in patients with metastatic malignant melanoma with DTIC 250 mg/m2 intravenously for 5 days alternating monthly with Piritrexim (PTX) using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Twenty-one patients were entered into the study. Among the 17 patients assessable for response, 1 patient had a minor response, and 3 patients had stable disease. No partial or complete response were observed. Toxicity was tolerable and consistent mainly of myelosuppression. Using this alternating dose schedule, PTX and DTIC produced little response in metastatic melanoma.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Middle Aged; Pyrimidines; Remission Induction
PubMed: 8526190
DOI: 10.1097/00000421-199512000-00006 -
European Journal of Cancer (Oxford,... 1994
Clinical Trial
Topics: Adult; Aged; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Pyrimidines
PubMed: 7946574
DOI: 10.1016/0959-8049(94)90156-2 -
Journal of Medicinal Chemistry Mar 1980The synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301U, 7) by a route that has general applicability to the preparation of many...
The synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301U, 7) by a route that has general applicability to the preparation of many 6-(substituted benzyl)-5-methylpyrido[2,3-d]pyrimidines is described. The key intermediate, 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (4), is converted to the 7-chloro compound 5 by treatment with a 1:1 complex of N,N-dimethylformamide--thionyl chloride, and 5 is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield 7. BW301U is a potent lipid-soluble inhibitor of mammalian dihydrofolate reductase and has significant activity against the Walker 256 carcinosarcoma in rats.
Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Cell Division; Folic Acid Antagonists; Humans; In Vitro Techniques; Leukemia, Myeloid; Male; Methotrexate; Pyrimidines; Rats
PubMed: 6928967
DOI: 10.1021/jm00177a025 -
The Journal of Infectious Diseases Nov 1987
Topics: Animals; Anti-Infective Agents; Drug Combinations; Drug Evaluation, Preclinical; Mice; Pyrimethamine; Pyrimidines; Sulfadiazine; Toxoplasma; Toxoplasmosis, Animal
PubMed: 3484324
DOI: 10.1093/infdis/156.5.828 -
Cancer Treatment Reports 1987
Topics: Aged; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Folic Acid Antagonists; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pyrimidines
PubMed: 3038318
DOI: No ID Found -
Virology Mar 2000Kaposi's sarcoma-associated herpesvirus (KSHV) is the first human virus known to encode dihydrofolate reductase (DHFR), an enzyme required for nucleotide and methionine... (Comparative Study)
Comparative Study
Kaposi's sarcoma-associated herpesvirus (KSHV) is the first human virus known to encode dihydrofolate reductase (DHFR), an enzyme required for nucleotide and methionine biosynthesis. We have studied the purified KSHV-DHFR enzyme in vitro and analyzed its expression in cultured B-cell lines derived from primary effusion lymphoma (PEL), an AIDS-associated malignancy. The amino acid sequence of KSHV-DHFR is most similar to human DHFR (hDHFR), but the viral enzyme contains an additional 23 amino acids at the carboxyl-terminus. The viral DHFR, overexpressed and purified from E. coli, was catalytically active in vitro. The K(m) of KSHV-DHFR for dihydrofolate (FH(2)) was 2.4 microM, which is significantly higher than the K(m) of recombinant hDHFR (rhDHFR) for FH(2) (390 nM). K(m) values for NADPH were similar for the two enzymes, about 1 microM. KSHV-DHFR was inhibited by folate antagonists such as methotrexate (K(i): 200 pM), aminopterin (K(i): 610 pM), pyrimethamine (K(i): 29 nM), trimethoprim (K(i): 2.3 microM), and piritrexim (K(i): 3.9 nM). In all cases, K(i) values for these folate antagonists were higher for KSHV-DHFR than for rhDHFR. The viral enzyme was expressed at levels two- to tenfold higher than hDHFR in PEL cell lines as an early lytic cycle gene. KSHV-DHFR mRNA and protein appeared from 6 to 24 h after chemical induction of the KSHV lytic cycle. Epitope-tagged KSHV-DHFR and rhDHFR both localized to the nucleus of transfected cells, while other KSHV nucleotide metabolism genes localized to the cytoplasm. DHFR activity was not essential for viral replication in cultured PEL cells. Since hDHFR was not detectable in peripheral blood mononuclear cells (PBMCs), KSHV-DHFR may function to provide increased DHFR activity in vivo in infected cells that have little or none of their own enzyme.
Topics: Amino Acid Sequence; Aminopterin; Butyrates; CD3 Complex; Enzyme Inhibitors; Herpesvirus 8, Human; Humans; Kinetics; Leukocytes, Mononuclear; Lymphoma, B-Cell; Molecular Sequence Data; RNA, Messenger; Sequence Analysis, Protein; Tetrahydrofolate Dehydrogenase; Tumor Cells, Cultured; Virus Replication
PubMed: 10683342
DOI: 10.1006/viro.1999.0165 -
Archives of Dermatology Apr 1992
Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Pilot Projects; Pyrimidines; Skin Neoplasms
PubMed: 1580670
DOI: No ID Found -
Journal of the National Cancer Institute Aug 1993
Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Resistance; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Male; Methotrexate; Neoplasm Recurrence, Local; Pyrimidines
PubMed: 8331686
DOI: 10.1093/jnci/85.15.1248 -
Cancer Metastasis Reviews 1987We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in... (Comparative Study)
Comparative Study Review
We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.
Topics: Animals; Cell Line; Drug Resistance; Folic Acid Antagonists; Humans; Methotrexate; Neoplasms; Structure-Activity Relationship
PubMed: 3549036
DOI: 10.1007/BF00047000 -
Current Pharmaceutical Design 2007Opportunistic infections are known to cause morbidity and mortality in immunocompromised individuals. In addition, serious infections due to several parasites are also... (Review)
Review
Opportunistic infections are known to cause morbidity and mortality in immunocompromised individuals. In addition, serious infections due to several parasites are also known to affect the quality and duration of life in normal individuals. The importance of dihydrofolate reductase (DHFR) in parasitic chemotherapy arises from its function in DNA biosynthesis and cell replication. DHFR catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), an essential cofactor in the biosynthesis of thymidylate monophosphate (dTMP). Inhibition of DHFR leads to a deficiency of dTMP since DHF cannot be recycled, and thus causes inhibition of cell growth. Methotrexate (MTX) and aminopterin (AMT) were among the first known classical inhibitors of DHFR. Trimethoprim (TMP) and pyrimethamine (PYR) are among the first known non classical inhibitors of DHFR. TMP and PYR are selective but weak inhibitors of DHFR from several parasitic organisms and coadministration of sulfonamides is required to provide synergistic effects for clinical utility. Unfortunately, the side effects associated with sulfa drugs in this combination often result in cessation of therapy. Trimetrexate (TMQ) and piritrexim (PTX) are two potent non classical inhibitors, neither of which exhibit selectivity for pathogen DHFR and must be used with host rescue. However, the current combination therapy suffers from high cost, in addition, several mutations have been reported in the active site of parasitic DHFR rendering the infections refractive to known DHFR inhibitors. The selectivity of TMP is a hallmark in the development of DHFR inhibitors and several efforts have been made to combine the potency of PTX and TMQ with the selectivity of TMP. Thus the structural requirements for DHFR inhibition are of critical importance in the design of antifolates for parasitic chemotherapy. Structural requirements for inhibition have been studied extensively and novel agents that exploit the differences in the active site of human and parasitic DHFR have been proposed. This review discusses the synthesis and structural requirements for selective DHFR inhibition and their relevance to parasitic chemotherapy, since 1995.
Topics: Animals; Antiparasitic Agents; Drug Delivery Systems; Folic Acid Antagonists; Humans; Tetrahydrofolate Dehydrogenase
PubMed: 17346178
DOI: 10.2174/138161207780162827