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

Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, was shown to be more active than its analogue, Methotrexate, against murine and human tumor cell lines in vitro and in vivo. We conducted two sequential phase I studies using a single bolus injection of TMTX every 14 days (Schedule A) and a weekly x 3 schedule every 4-6 weeks (Schedule B). Twenty-seven patients were treated on Schedule A with a TMTX dose range of 5 mg/m2 to 450 mg/m2 and 23 patients were treated on Schedule B with a TMTX dose range of 50 mg/m2 to 200 mg/m2. The dose limiting toxicity was myelosuppression on both schedules. The development of hematological toxicity was highly variable at different dose levels and within the same patient at a particular dose level. The nadir of blood counts was reached by Day 8 to 10 on the single dose schedule with recovery by Day 14. On Schedule B, the nadir granulocyte count occurred on Day 14 while platelet count was generally lowest by Day 20; the blood counts usually recovered 7 to 10 days after the last dose. Other common side-effects includes skin toxicity and stomatitis which were worse on the weekly schedule. Less common toxicities included mild nausea and vomiting, diarrhea, and transient deterioration in renal and hepatic functions. The occurrence of toxicity was not related to the extent of prior treatment, liver metastases, or accumulation of third space fluids. Based on our results, we recommend a starting TMTX dose for Phase II studies of 200 mg/m2 every 2 weeks or 100 mg/m2 to 125 mg/m2 on the weekly schedule.
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PMID:Phase I studies of trimetrexate using single and weekly dose schedules. 183 42

Between June and October 1982, Vibrio cholerae el tor Inaba phage type Russian 13, resistant to ampicillin (Ap), chloramphenicol (Cm), colistin, neomycin (Nm), kanamycin (Km), gentamicin (Gm), trimethoprim sulfamethoxazole (TMP-SMZ), and tetracycline (Tc), was isolated from 31 children with diarrhea at a hospital in Samutsakorn, Thailand. Thirty of these children were less than 2 years of age and were admitted to a single pediatric ward. Seventeen of the cases, infected with V. cholerae (MARV) resistant to several antibiotics, were admitted to the hospital for non-gastrointestinal illnesses; these children developed diarrhea and positive cultures for MARV 1-greater than 10 days after admission. The majority of cases occurred in September, when the attack rate in the patient population in 1 pediatric ward was 11.5%. During this period, MARV with the same characteristics was isolated from water used for bathing in a reservoir on the pediatric ward where most of the cases occurred. MARV was not isolated from adults with diarrhea at the hospital. No further MARV infections occurred at the hospital after the water reservoir had been drained and disinfected. V. cholerae isolates from children and water contained a conjugative incompatibility group C plasmid of 100 megadaltons (mDa) encoding resistance to Ap, Cm, Nm, Km, Gm, TMP-SMZ, and Tc. This plasmid hybridized with a DNA probe for genes encoding Type II dihydrofolate reductase (DHFR). As far as we know, this is the first report of MARV with V. cholerae that contained genes coding for Type II DHFR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An epidemic of Vibrio cholerae el tor Inaba resistant to several antibiotics with a conjugative group C plasmid coding for type II dihydrofolate reductase in Thailand. 264 46

Plasmid pUN835 was identified in an Escherichia coli strain isolated from an outbreak of porcine diarrhoea on a farm near Nottingham, UK. The trimethoprim resistance gene did not hybridize with any of the gene probes derived from known plasmid-encoded trimethoprim resistance genes. The trimethoprim resistance gene of pUN835 was shown to encode the production of a dihydrofolate reductase which confers high-level resistance on its host. This enzyme was smaller than most plasmid-encoded dihydrofolate reductases (molecular mass = 11,500) and was labile to heat. It had relatively low affinity for the substrate dihydrofolate (Km = 20 microM) and it was resistant to competitive inhibition by trimethoprim (Ki = 7.0 microM). We classify this novel enzyme as type VII.
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PMID:The type VII dihydrofolate reductase: a novel plasmid-encoded trimethoprim-resistant enzyme from gram-negative bacteria isolated in Britain. 267 36

Several chemotherapeutic protocols for the treatment of malignancies include administration of methotrexate (MTX) during or shortly after total anesthesia. Clinical observations in patients treated for breast carcinoma or childhood cancer have shown unexpected myelosuppression and mucosal damage. This phenomenon may be attributed to the synergistic effects of nitrous oxide, which inactivates the cobalamin coenzyme of methionine synthase, and MTX, which inhibits dihydrofolate reductase, on folate metabolism. However, no quantitative data on dose-effect relationships are available regarding the combined toxicity of MTX and N2O. We investigated the effect of exposure to N2O on the toxicity of MTX. Groups of male Wistar rats were exposed to either 50% N2O/50% O2 or air for 12-48 h. Subsequently, a single i.p. injection of 10, 20, 40, or 80 mg MTX/kg body weight was given. Gastrointestinal toxicity resulted in diarrhea and weight loss in all groups for 5 days after MTX administration. Concomitantly, bone marrow depression with leukocytopenia and thrombocytopenia occurred. Exposure to N2O did not alter the plasma clearance of MTX. No substantial liver or kidney toxicity could be detected, but the 50% lethal dose for MTX was reduced from 60 mg/kg to 10 mg/kg if rats had been exposed to N2O for 48 h; the main causes of death were dehydration and bleeding. The administration of 5-formyl-tetrahydrofolate (4 x 10 mg i.p.) but not 5-methyltetrahydrofolate protected completely against the lethal effect of the drug combination. Altogether, cytotoxic effects of MTX on proliferating cells are potentiated by N2O. Therefore, the use of this anesthetic shortly before or during MTX administration should be avoided.
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PMID:Toxicity of methotrexate in rats preexposed to nitrous oxide. 280 78

Trimetrexate (TMQ; NSC 352122) is a potent inhibitor of dihydrofolate reductase with good activity against murine i.p.-implanted B16 melanoma and colon 26 tumors. Preclinical antineoplastic activity, demonstrated schedule dependency, and data suggesting effectiveness against methotrexate-resistant cells prompted a Phase I clinical and pharmacokinetic study of trimetrexate using an i.v. daily x5 schedule. Forty-three good performance status patients were treated with 12 dose levels using daily doses varying from 0.5 to 15 mg/m2/d. Plasma and urine samples were obtained for pharmacokinetic analysis using a high-performance liquid chromatographic method. Myelosuppression was dose limiting and 15 mg/m2/d x5 was the maximum tolerated dose. White blood cell (WBC) and platelet toxicity were noted at doses of 1.6 mg/m2 and above. Median WBC and platelet nadirs occurred on approximately Days 11-12 with recovery by Days 15-18. Nonhematological toxicity included mucositis, nausea and vomiting, stomatitis, diarrhea, and rash. Evidence for antitumor activity was seen in seven patients. Trimetrexate elimination from plasma could be represented as either a bi- or triexponential process. Terminal elimination half-lives were in the range of 5-14 h in patients represented by a triexponential model. Approximately 10-20% of the dose administered was excreted in urine over a 24-h period. The recommended starting dose for patients in Phase II trials using the d x5 i.v. schedule is 8.0 mg/m2/d repeated every 21 days. Dose escalations may be possible depending on the extent of prior therapy and individual tolerance of the drug.
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PMID:Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule. 297 Feb 94

Vibrio cholerae biotype el tor strain BM2508, resistant to trimethoprim, 0/129, streptomycin and spectinomycin was isolated from the faeces of a child with severe diarrhoea. Resistance to trimethoprim and 0/129 was due to a dihydrofolate reductase type I and resistance to streptomycin-spectinomycin to a 3'',9-aminoglycoside-aminocyclitol adenylyltransferase. The resistance genes were not transferable to Escherichia coli and, as inferred from ultracentrifugation in cesium chloride-ethidium bromide and agarose gel electrophoresis of crude bacterial lysates, were located on the chromosome. The resistance genes were transposed to multiple sites of plasmids belonging to incompatibility groups 6-C and P, introduced in BM2508 and were subsequently transferred to E. coli (rec-), Salmonella typhimurium, V. cholerae and V. parahaemolyticus strains where they re-transposed into the chromosome. Analysis of plasmid DNA from the transconjugants by agarose gel electrophoresis following digestion with HindIII and by Southern hybridization using a ColEl::Tn7 probe indicated the presence of a 14-kilobase transposon, Tn1527, closely related to Tn7. The emergence of Tn1527 in V. cholerae may lead to prophylactic and therapeutic failures due to trimethoprim resistance and to bacterial misidentification because of cross resistance to 0/129.
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PMID:Transposable resistance to trimethoprim and 0/129 in Vibrio cholerae. 301 28

The percentage of Shigella and enterotoxigenic Escherichia coli (ETEC) strains resistant to trimethoprim (TMP)-sulfamethoxazole isolated from children with diarrhea at the outpatient department of the Children's Hospital in Bangkok increased from 3 and 0%, respectively, in 1982 to 29% and 25% in 1986. One hundred thirty-nine Shigella and 22 ETEC strains resistant to greater than 1024 micrograms/ml of trimethoprim (TMPr) isolated from children with diarrhea in Bangkok in 1984 and 1985 were analyzed for the presence of type I, II and III plasmid-specific dihydrofolate reductase (DHFR) genes. Thirty-two percent (45 of 139) of TMPR Shigella had genes encoding type II and 9% (13 of 139) had genes encoding type I DHFR genes. Fifty percent (11 of 22) of TMPR ETEC had type II and 14% (3 of 22) had type I DHFR genes. Plasmids encoding DHFR were identified by the Southern technique in 24% (14 of 58) of Shigella and 1 of 14 ETEC that contained genes encoding DHFR. Plasmids coding for type II DHFR were transferred to E. coli K12 by conjugation from 13 of 14 Shigella and a plasmid coding for type I DHFR was transferred from the single ETEC containing a plasmid coding for type I DHFR. Genes coding for DHFR were presumably situated on the chromosome in 76% (44 of 58) of Shigella and 93% (13 of 14) of ETEC that contained genes encoding DHFR. Since 58% (81 of 139) of TMPR Shigella and 36% (8 of 22) of TMPR ETEC strains examined did not contain genes encoding type I, II or III DHFR, high level TMP resistance was presumably caused by other types of DHFR genes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Trimethoprim-resistant Shigella and enterotoxigenic Escherichia coli strains in children in Thailand. 331 33

A previous study revealed the emergence of high-level resistance to trimethoprim-sulfamethoxazole in strains of Escherichia coli isolated from 95% of students from the United States who were taking either trimethoprim alone or trimethoprim-sulfamethoxazole for prophylaxis of travelers' diarrhea while in Guadalajara, Mexico. Many of these strains were subsequently demonstrated to cotransfer resistance to trimethoprim along with that to streptomycin and ampicillin. The present study demonstrated that at least 12 (60%) of 20 transferable (tra+) trimethoprim-resistance plasmids studied possessed both an identical Hind III restriction pattern and type I dihydrofolate reductase genes. Donor strains were shown to be distinct; this finding suggested that a common tra+ trimethoprim-resistance plasmid was widely disseminated among E. coli strains in Guadalajara. These results may explain in part the surprising degree of resistance encountered in trimethoprim-consuming persons in that region.
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PMID:Evidence for an epidemic trimethoprim-resistance plasmid in fecal isolates of Escherichia coli from citizens of the United States studying in Mexico. 608 71

The pharmacology of trimetrexate (JB-11, NSC 249008, 2,4-diamino-5-methyl-5-[(3,4,5-trimethoxyanilino)methyl]quinazoline), an antitumor agent effective against several mouse tumors, was studied in normal dogs. A high-performance liquid chromatographic technique with electrochemical detection, dihydrofolate reductase inhibition assay, and 14C-labeled drug were used to measure plasma disappearance, tissue distribution, excretion, and metabolism of the drug at doses from 0.5 to 6 mg/kg. Doses of 2 mg/kg were well tolerated without toxicity. Higher doses (3 to 6 mg/kg) produced mainly intestinal toxicity without significant hematological or liver abnormalities. The 6-mg/kg dose caused severe bloody diarrhea. After administration of 3 mg/kg, plasma concentrations of trimetrexate were 1 microM and were equal to or greater than 0.1 microM at 1 and 24 hr, respectively. The predominant pharmacokinetics of trimetrexate plasma disappearance was an elimination phase with a t1/2 of 3.5 hr. Concentrations in the cerebrospinal fluid were 2 to 5% of that in plasma and were maximum within 1 to 2 hr after i.v. administration. Highest tissue concentrations of drug were measured in liver and kidney; lowest were found in brain and lung. A dose equivalent to 3 mg/kg in humans (on a sq m basis) should produce adequate plasma concentrations (greater than 0.1 microM) for therapeutic effects.
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PMID:Pharmacology and toxicity of a potent "nonclassical" 2,4-diamino quinazoline folate antagonist, trimetrexate, in normal dogs. 646 9

Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.
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PMID:Incorporation of pemetrexed (Alimta) into the treatment of non-small cell lung cancer (thoracic tumors). 1209 34


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