Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory effects of N10-propargyl-5,8-dideazafolic acid (CB3717), a quinazoline antifolate and a potent thymidylate synthase inhibitor, were evaluated in human leukemia cell lines resistant to methotrexate (MTX) and trimetrexate (TMQ). MTX-resistant MOLT-3 cell lines, MOLT-3/MTX200 and MOLT-3/MTX10,000, were cross-resistant to CB3717; however, the degree of resistance was only tenfold for both cell lines, and increased dihydrofolate reductase activity in MOLT-3/MTX10,000 had little influence on the degree of CB3717 resistance. The MOLT-3 cell line made resistant to TMQ, MOLT-3/TMQ200, was as sensitive to CB3717 as the parent line. The cell growth inhibitory effect of CB3717 on MOLT-3 was reversed by the addition of thymidine. Leucovorin also partially reversed CB3717-induced growth inhibition. Cellular uptake of MTX and 5-methyl-tetrahydrofolate was hindered by the presence of a high concentration of CB3717, whereas TMQ uptake was not influenced by CB3717. CB3717 appears to enter the cells not only through reduced folate transport system, but by other route(s). CB3717 does not share the transport pathway with TMQ. Our observations that MTX-resistant cells with increased dihydrofolate reductase are not more resistant than cells without increased enzyme activity, and that TMQ-resistant cells are not cross-resistant to CB3717, may have clinical relevance.
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PMID:N10-propargyl-5,8-dideazafolic acid (CB3717): inhibitory effects on human leukemia cell lines resistant to methotrexate or trimetrexate. 143 41

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.
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PMID:Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group. 189 77

We have tested folinic acid (FA) for ability to increase peripheral blood stem cells (PBSC) after chemotherapeutic aplasia in acute leukaemia. Five adult patients (four AML, one ALL) entered the study, each patient underwent two series of three leukapheresis, the first following induction chemotherapy and the second following the first course of consolidation. The first leukapheresis of each series was done when the white blood cell count reached 10(9)/l with subsequent leukapheresis every other day. Folinic acid (Lederle Laboratories, France) was administered at a dose of 50 mg (i.v.) per day, 15 days from initiation of chemotherapy and continuing through the third leukapheresis of the series (days 25-30). PBSC were collected on a Haemonetics V50 cell separator. In these five cases we observed an increased yield of both colony-forming units, granulocyte macrophage (CFU-GM) and burst forming units-erythroid (BFU-E) expressed per ml of cytapheresis product: CFU-GM x 18, BFU-E x 3 and if expressed per 10(4)/kg of body weight: CFU-GM x 30, BFU-E x 3 (CFU-GM P less than 0.05, BFU-E less than 0.01). Long-term blood culture (LTSC) from FA stimulated leukapheresis, in an attempt to quantitate the most primitive stem cells, demonstrated that this expansion of the PBSC was sustained in time. We found by means of LTSC that FA did not stimulate CFU-L from patients with AML (two cases tested). Finally two AML patients were grafted with FA-PBSC after Cytotoxan and total body irradiation (TBI). Haematopoietic reconstitution was rapid complete and sustained in time in both patients. This indication for folinic acid should be further studied with or as an alternative to haematopoietic growth factors.
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PMID:Expansion by folinic acid of the peripheral blood progenitor pool after chemotherapy: its use in autografting in acute leukaemia. 204 85

Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.
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PMID:Biochemical pharmacology of the lipophilic antifolate, trimetrexate. 623 75

A study was performed to determine whether the addition of folinic acid to a combination of methotrexate (MTX) and cyclosporin A (CsA) after allogeneic bone marrow transplantation (BMT) could improve tolerance to the regimen without inhibiting its ability to prevent graft-versus-host disease (GVHD). Sixty-nine adult BMT patients received CsA plus MTX 15 mg/m2 on day 1 and 10 mg/m2 on days +3, +6 and +11. Folinic acid 5 mg was started 24 h after each MTX dose and continued 6 hourly until 12 h before the next dose of MTX. The median age of the group was 37 years and 13 patients (19%) received bone marrow from mismatched and/or unrelated donors. No MTX doses were omitted or modified. Grade II-IV acute GVHD occurred in 18 patients (29%) and chronic GVHD in 35 of 56 (64%) patients at risk. There were no cases of grade > or = III stomatitis. Transplant-related mortality was 7% before 100 days and 20% overall (9% for low risk leukaemia) with a median follow-up of 41 months (range 24-88 months). This regimen of folinic acid rescue may contribute to a well tolerated GVHD prophylaxis protocol with reasonably low BMT-related mortality. Our results suggest that the ability of MTX to prevent acute GVHD is not abrogated by folinic acid given in this way.
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PMID:Addition of low-dose folinic acid to a methotrexate/cyclosporin A regimen for prevention of acute graft-versus-host disease. 799 61

Fluoroglutamate-containing analogs of folates and methotrexate (MTX) with altered capacities for poly (gamma-glutamate) metabolism were synthesized to probe the biological roles of polyglutamates. Compared to folic acid, DL-e,t-gamma-fluorofolic acid, a compound that is a poor substrate for polyglutamylation, was approximately 25-fold less potent in promoting growth of folate-depleted H35 rat hepatoma cells. DL-beta,beta-Difluorofolic acid, a compound that forms diglutamates more readily than does folic acid, was at least equivalent to folic acid in potency. Leucovorin (LV), a reduced folate, was 30-fold more potent than folic acid in promoting growth, whereas the analogous form of DL-e,t-gamma-fluorofolate, DL-e,t-gamma-fluoroleucovorin (DL-e,t-gamma-FLV) was only 4-fold more potent than folic acid. Both LV and DL-e,t-gamma-FLV protected or "rescued" cells from the growth inhibitory effects of MTX; however a 37- to 46-fold higher concentration of the fluoro analog was required. Folic acid, DL-e,t-gamma-fluorofolic acid, LV, and DL-e,t-gamma-FLV each potentiated the growth inhibitory effect of 5-fluoro-2'-deoxyuridine on CCRF-CEM human leukemia cells; higher concentrations of fluorinated analogs again were required. Stereochemically pure L-t-gamma-fluoromethotrexate (L-t-gamma-FMTX), a poor substrate for polyglutamylation, was evaluated as a cell growth inhibitor. In continuous exposure, L-t-gamma-FMTX), was 7-fold less potent than MTX as an inhibitor of CCRF-CEM growth. Results with these fluorinated folate and MTX analogs offer insight into the importance of polyglutamate metabolism to these biological and pharmacological effects.
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PMID:Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (gamma-glutamate) metabolites. 893 38

Methotrexate (MTX), an anticancer compound, is widely used in the treatment of leukemia. It induces cytogenetic damage as well as cytostatic effects on a variety of cell systems. Folinic acid (Leucovorin) is generally administered along with MTX as a rescue agent to decrease MTX-induced toxicity. However, information regarding the inhibitory effect of folinic acid against cytogenetic damage caused by MTX is limited. This study was conducted to assess the cytogenetic effect of MTX and its inhibition by folinic acid (FA) using the micronucleus and chromosomal aberration assays concurrently. Exponentially growing V79 cells were treated with MTX at five different concentrations (5-100 micrograms ml-1) with S9 microsomal fraction for 6 h and post-treated with two concentrations of FA (5 or 50 micrograms) for 40 h. Results indicate that MTX alone induced a concentration-related increase in % micronucleated binucleated cells (MNBN) and % aberrant cells (Abs). There was a decrease in nuclear division index (NDI) with increase in MTX concentration. Similarly, the mitotic index (MI) also decreased in all concentrations of MTX tested. The addition of FA at 50 micrograms ml-1 significantly reduced % MNBN (40-68%) and % Abs (36-77%). Inhibition was also seen at 5 micrograms FA (12 to 54% for MNBN and 20 to 61% for Abs). These results indicate that FA is capable of reducing the cytogenetic damage induced by MTX and appears to be an anticlastogenic agent.
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PMID:Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells. 954 46

In patients with colon cancer who undergo resection for potential cure, 40% to 60% have advanced locoregional disease and are classified as either stage II or stage III. The role of adjuvant therapy in stage III colon cancer is well defined. The results from the MOSAIC trial (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) and the National Surgical Adjuvant Breast and Bowel Project C-07 trial confirm a definite disease-free survival (DFS) benefit with the addition of oxaliplatin to either infusional or bolus 5-fluorouracil/leucovorin (5-FU/LV). The Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial showed capecitabine to be of equivalent clinical benefit to bolus 5-FU/LV. However, adjuvant trials with irinotecan, including Cancer and Leukemia Group B (CALGB 89803), the Pan-European Trial in Adjuvant Colorectal Cancer 3 (PETACC-3), and the French ACCORD trial, have not shown a significant DFS advantage. In contrast, in patients with stage II disease, a small survival benefit of 1% to 5% exists with chemotherapy. Perhaps the analysis of molecular markers in combination with high-risk histopathologic features will help increase patient specificity and identify subsets of patients with stage II colon cancer who will derive a survival benefit with adjuvant therapy. The current Intergroup study stratifying stage II patients based on presence of microsatellite instability and loss of heterozygosity 18q allele will help us better understand the risk versus benefit observed.
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PMID:Adjuvant therapy for colon cancer. 1799 44

alpha-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.
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PMID:Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid. 1966 84

We report a case of a 79-year-old man who developed severe therapy-related pancytopenia from tegafur uracil(UFT)and Leucovorin(LV)as adjuvant chemotherapy for ascending colon cancer. Laparoscopic right hemicolectomy resection was performed for the ascending colon cancer. Pathohistological analysis revealed that the ascending colon tumor was moderately differentiated tubular adenocarcinoma(T3, N1, M0, and Stage III a). Postoperative adjuvant chemotherapy with UFT and LV was administered. After 2 courses of chemotherapies, severe thrombocytopenia(Grade 4)and neutropenia(Grade 4)were noted. Platelet and granulocyte-colony stimulating factor(G-CSF)were transfused. Furthermore, red blood cell transfusions were given for anemia(Grade 3). Dihydropyrimidine dehydrogenase(DPD)deficiency was suspected as the cause of the pancytopenia, and the ratio of dihydrouracil(DHU)and uracil(URA)was measured. However, the result was negative for DPD deficiency. Bone marrowaspiration revealed that therapy-related leukemia(TRL)and therapy-related myelodysplastic syndrome(T-MDS)were not the causes of the pancytopenia either. A total of 230 units of platelet transfusions and 20 units of red blood cell transfusions have been given for 32 weeks, and the patient currently requires routine blood transfusions. Fortunately, infection and bleeding never occurred. Subsequently, the patient should be monitored carefully.
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PMID:[Severe Therapy-Related Pancytopenia Caused by UFT and LV in a Patient with Ascending Colon Cancer]. 2939 47


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