Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ANTIMETABOLITES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed1998

Delayed corneal epitheliopathy after antimetabolite-augmented trabeculectomy.

PURPOSE: The authors describe the first case of delayed antimetabolite-related corneal epithelial toxicity after trabeculectomy and its successful treatment with limbal stem cell transplantation. METHODS: A 73-year-old woman underwent trabeculectomy with intraoperative mitomycin C. After surgery she received six 5-mg injections of subconjunctival 5-fluorouracil (5-FU) adjacent to the bleb. RESULTS: The patient had a functioning trabeculectomy and clear cornea until 30 months after surgery, at which time she developed a nonhealing superior corneal epithelial defect. After 4 months of conservative medical management, an autologous limbal stem cell transplantation was performed. The epithelial defect resolved completely within 1 week of limbal stem cell transplantation. CONCLUSIONS: Delayed corneal epithelial toxicity may be a late complication of antimetabolite-augmented trabeculectomy.

Aged↗
PubMed1975

Combined androgen and antimetabolite therapy of advanced female breast cancer. A report of the cooperative breast cancer group.

A clinical trial of androgen and antimetabolite therapy of advanced female breast cancer was conducted in 110 patients by the Cooperative Breast Cancer Group. An objective regression rate of 20% was achieved in women receiving oral testolactone, 6% in patients given intravenous fluorouracil alone, and 14% when the androgen and antimetabolite were administered together. This randomized trial according to the CBCG protocol did not produce the high regression rate noted previously in a nonrandomized, nonprotocol evaluation of these drugs.

Administration, Oral↗
PubMed1975

Effects of thiamine antagonists on nerve conduction. II. Voltage clamp experiments with antimetabolites.

Thiamine antimetabolites were externally applied to voltage clamped squid giant axons to investigate the possible role of thiamine in nerve conduction. Phenylthiazinothiamine, in concentrations as low as 250 muM, reduced peak early current and steady-state current, with the depression of the former being two to five times greater than that of the latter. Peak transient and steady-state conductances were about equally depressed by thiamine tert-butyl disulfide (2 mM) and L-586944-00P07 (5-10 mM). None of the antimetabolites produced an appreciable change in the kinetics of Na+ activation, K+ activation, or Na+ inactivation. Thiamine itself, applied externally up to 30 mM, had no appreciable effect on either the magnitude or time course of the ionic currents. Although these data are consistent with the hypothesis that thiamine may be involved in nerve conduction, they probably reflect a nonspecific stabilizing interaction of this class of compound with the axon membrane. Taken in this light, the hypothesis that thiamine plays a direct role in Na+ channel permeability changes must be reevaluated.

Animals↗
PubMed1992

A novel anticancer treatment for xenoplanted human gastric cancer using polyamine antimetabolites in a low polyamine diet.

The aim of the present study was to evaluate a new anticancer treatment for gastrointestinal cancer, using a combination of polyamine antimetabolites, an anticancer agent and a low-polyamine state. Two polyamine antimetabolites, given as either 40 mg/kg of methylglyoxal-bis-guanylhydrazone (MGBG) or ethylglyoxal-bis-guanylhydrazone (EGBG) and a normal diet (ND), or 20 mg/kg of each drug and a low polyamine diet (LPD), together with 1,000 mg/kg of alphadifluoromethylornithine (DFMO) were administered ip to nude mice for six consecutive days. Mitomycin C (MMC) at 2 mg/kg was then given ip for 3 alternate days. The combination of MGBG or EGBG with DFMO plus MMC resulted in an enhanced antitumor efficacy on LPD. However, the combination which included EGBG was much more enhanced than that which included MGBG and there was no evidence of any tumor regrowth. Weight loss was minimal or nil in the mice given the combination with EGBG, but was evident in those given the combination with MGBG. These results led to the conclusion that in mice, the combined therapy of EGBG with DFMO plus MMC and LPD is a safe and effective regimen for the treatment of gastric cancer.

Adenosylmethionine Decarboxylase↗
PubMed1987

Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites.

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.

Adenocarcinoma↗
PubMed1991

Organ culture as a model for investigating the effects of antimetabolites and nucleoside transport inhibitors on rodent colonic mucosa.

The in-vitro effects of hydroxyurea 5-FU and 5-FUdR have been extensively studied in experimental systems employing cell-line techniques. In this study we investigated the effects of these drugs on the levels of incorporation of labeled nucleosides into DNA in explants of intact rat colonic mucosa maintained in organ culture. The effects of the nucleoside transport inhibitors nitrobenzylthioinosine (NBMPR) and dipyridamole--which are modulators of antimetabolite cytotoxicity--on the incorporation of tritiated thymidine ([3H]TdR) into DNA were also studied. The incorporation of tritiated TdR into DNA was reduced by hydroxyurea but was not altered by either 5-FU or 5-FUdR. The levels of tritiated deoxyuridine were reduced by 5-FU and 5-FUdR in separate experiments; this is in keeping with thymidylate synthase inhibition. NBMPR and dipyridamole also reduced 3H-TdR incorporation into DNA. These results can be explained in terms of the known mechanisms of action of these drugs. This experimental model is therefore useful in assessing the effects of antimetabolites and nucleoside transport inhibitors in intact colonic mucosa.

Animals↗
PubMedDate not supplied

Pathologic effects of antimetabolites on the hippocampus of diet controlled mice.

Marked histological changes are observed in the hippocampi of mice maintained on a niacin deficient diet following a single injection of 3-acetylpyridine (antimetabolite of nicatinamide). Extensive neuronal damage occurs in areas H2, H3 and to a lesser degree in the dentate gyrus. The neurons appear to be shrunken, deeply basophilic and exhibit a loss of intracellular architecture. The neuronal response in pyridoxine deficient mice treated with 4-methoxypyridoxine (antimetabolite of pyridoxine) is not remarkable.

Animals↗
PubMed1992

Long-term results of trabeculectomy with collagen sponge implant containing low-dose antimetabolite.

Eighteen eyes of 15 patients with uncontrolled glaucoma (neovascular, intracapsular aphakia, uveitic, previous filtration failure) at high risk for failure of standard filtration underwent trabeculectomy with implantation of a purified collagen sponge containing 100 micrograms of antimetabolite (5-fluorouracil or bleomycin). Follow-up ranged from 3 months to 5 years. At the end of follow-up, 14 eyes (78%) had intraocular pressure below 21 mmHg and functional filtration blebs. No corneal toxicity was encountered at any time. Two patients (both successes) had partial or complete erosion of the collagen sponge. Although the differences were not statistically significant, patients receiving bleomycin had better success rates (8 of 9 versus 6 of 9) and lower intraocular pressure levels (11.88 mmHg versus 14.63 mmHg) than those receiving 5-fluorouracil. The collagen sponge implant demonstrates the clear advantages of drug delivery devices for the administration of antimetabolites after filtration surgery.

Adult↗
PubMed1992

Antimetabolites.

Research efforts over the past year further elucidate the determinants of sensitivity and mechanisms of resistance to the antimetabolites fluorouracil, methotrexate, and cytarabine. Progress has been made in clarifying the complex regulation of target enzyme expression for these antimetabolites. Advances in analytical methodology should facilitate quantitation of thymidylate synthase content in tumor tissue prior to and following fluorouracil-based therapy. Information concerning the basis for certain drug interactions may guide rational dose rates and schedules for clinical trials. A better understanding of the clinical pharmacology of these agents has suggested strategies to minimize their toxicity while maintaining therapeutic activity.

Animals↗
PubMed1979

Modulation of cytochrome biosynthesis in yeast by antimetabolite action of levulinic acid.

Levulinic acid, a competitive inhibitor of delta-aminolevulinic acid dehydratase, was used to inhibit cytochrome biosynthesis in growing yeast cells. In Saccharomyces cerevisiae the antimetabolite acts by inhibiting delta-aminolevulinic acid dehydratase in vivo, causing an accumulation of intracellular delta-aminolevulinic acid and simultaneous decreases in all classes of mitochondrial cytochromes. Changes in cellular cytochrome content with increasing levulinic acid concentration suggested the existence of different regulatory patterns in S. cerevisiae and Candida utilis. In C. utilis, cytochrome a.a3 formation is very resistant to the antimetabolite action of levulinic acid. In this aerobic yeast, cytochrome c+c1 is the most sensitive to levulinic acid, and cytochrome b exhibits intermediate sensitivity.

Candida↗
PubMedDate not supplied

A phase I study of the antimetabolite (E)-2'-fluoromethylene-2'-deoxycytidine (MDL 101,731) administered as a twice-weekly infusion.

PURPOSE: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule. PATIENTS AND METHODS: The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients. RESULTS: Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred. DISCUSSION: (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2.

Adult↗
PubMed1985

Effect of antimetabolites and thymidine blockage on the induction of differentiation of HL-60 cells by retinoic acid or 1 alpha,25-dihydroxyvitamin D3.

Induction of differentiation of the HL-60 human promyelocytic leukemia cell line by retinoic acid or 1 alpha,25(OH)2D3 was analyzed under the condition in which cellular DNA synthesis was inhibited by several antimetabolites or blocked by thymidine. The results demonstrate that differentiation occurs in the absence of DNA synthesis and that some inhibitors of DNA synthesis may enhance the differentiation of HL-60 cells by the above inducers. Among the antimetabolites used, the enhancement of induction of differentiation by hydroxyurea was shown to be more effective than that of Ara-C or aphidicolin. The effect of thymidine blockage was similar to that of hydroxyurea. These different effects may be due to the different points at which the cell cycle is blocked by these agents. These results seem to be common in both the differentiation of the granulocytic line induced by retinoic acid and of the macrophage line induced by 1 alpha,25(OH)2D3. The present study also suggests that combination treatment with the inhibitor of DNA synthesis and the inducer of differentiation could be beneficial in the clinical therapy of leukemia. The mode of action of clinical low-dose Ara-C treatment is also discussed.

Antibiotics, Antineoplastic↗
PubMed1993

Sensitivity of human KB cells expressing platelet-derived endothelial cell growth factor to pyrimidine antimetabolites.

Thymidine phosphorylase (dThdPase) is an enzyme involved in pyrimidine nucleoside metabolism. However, little is known about its physiological functions. We previously purified dThdPase from human placenta, isolated a complementary DNA clone for this enzyme, and sequenced it. There was complete sequence identity between 120 amino acids of human dThdPase and the sequence of platelet-derived endothelial cell growth factor (PD-ECGF). Human KB epidermal carcinoma cells transfected with platelet-derived endothelial cell growth factor complementary DNA expressed a 55-kDa protein that was detected with anti-dThdPase antibody and the cell lysate had dThdPase activity. The sensitivity of transfected cells to the antimetabolites was compared with that of untransfected KB cells. The sensitivity of the transfected cells to Doxifluridine (5'-deoxy-5-fluorouridine) was higher than that of untransfected KB cells. Transfected cells were also more sensitive to Tegafur than untransfected KB cells. These results demonstrate that dThdPase is involved in the activation of these anticancer agents. Since many cancer tissues contain high dThdPase activity compared with normal tissues, these transfected and untransfected KB cells are useful for studying the role of dThdPase in the activation of pyrimidine antimetabolites and also in angiogenesis.

Cell Division↗
PubMed1964

THE DEMONSTRATION OF THE SITE OF ACTION OF THE ANTIMETABOLITE DRUG 6-AZAURIDINE BY THE USE OF LEUCOCYTE CULTURES.

The ability of the lymphocyte cultured in vitro to transform and synthesize deoxyribonucleic has been utilized to locate the site of action of a new antimetabolite 6-azauridine which acts by inhibiting nucleic acid synthesis. The exact site can be demonstrated by incorporating into the cultures nucleotides occurring distal and proximal to the presumed site of action of 6-azauridine.

Antimetabolites↗
PubMed1964

ASSAY OF VITAMINS AND AMINO ACIDS WITH CULTURED TISSUE CELLS AND ANTIMETABOLITES.

A survey of growth responses of tissue-culture cells to vitamins and amino acids was undertaken to explore the potentialities of tissue culture in the assay of growth factors. An antagonist of the nutrient was included in each test system to improve its sensitivity. Addition of an antimetabolite was advantageous in the thiamine and phenylalanine assays. Tissue-culture assays of tryptophan and of phenylalanine supplemented with beta-2-thienylalanine compared favorably with microbial assays, and may serve as confirmatory or supplementary test systems. The sensitivity of cultured tissue cells to minute amounts of a variety of physiologically active substances suggests their employment in hormone and toxic compound assays.

Amino Acids↗
PubMed2002

Antimetabolite incorporation into DNA: structural and thermodynamic basis for anticancer activity.

Antimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes. In this review, the recent literature describing investigations of the structural and thermodynamic basis for the anticancer activity of three antipyrimidines [1-beta-D-arabinofuranosyl cytidine (AraC). 2',2'-difluoro deoxycytidine (dFdC), and 5-fluoro-2'-deoxyuridine (FdUrd)] is summarized. Our laboratory, and others, have shown that misincorporation of any of these three antipyrimidines into DNA perturbs the structure and decreases the stability of duplex DNA. These data are useful for rationalizing the effects of antipyrimidine misincorporation on the activities of proteins required for DNA replication and repair such as DNA topoisomerase 1 and DNA polymerases. The studies completed to date and summarized in this review demonstrate the utility of investigations into the structure-function relationships between antipyrimidine-substituted DNA complexed with DNA-modifying proteins for the purpose of understanding the basis for effective antipyrimidine cancer chemotherapy and the future design of novel anticancer drugs.

Antimetabolites, Antineoplastic↗
PubMed2006

t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.

BACKGROUND: The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1. METHODS: The current study describes what to the authors' knowledge is the first large case series reported to date of 26 t(3;21)(q26;q22)-associated leukemias, in which 24 cases arose after chemotherapy. Conventional G-band karyotyping and flow cytometry immunophenotyping were performed. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect fusion transcripts between AML1 and EAP, MDS1, or EVI1, followed by DNA sequencing. RESULTS: In all 16 patients with chronic myeloproliferative disorders, including 14 with chronic myelogenous leukemia (CML), the occurrence of t(3;21) heralded myeloid blast transformation. Fifteen (93%) patients had been previously treated with hydroxyurea. Eight patients with chronic myeloproliferative disorders (CMPD) were found to have t(3;21) with t(9;22) as the sole cytogenetic abnormality; in 5 other patients this was accompanied by trisomy 8. Among 10 cases of t(3;21)-associated acute myeloid leukemia, 8 were secondary tumors after chemotherapy for other neoplasms that had been treated with regimens including fludarabine and 5-fluorouracil in 3 patients each and etoposide in 2 patients. The immunophenotype of the blasts in all 22 tested cases was similar, with uniform expression of myeloid markers and CD34 and variable expression of CD7 and CD9, but minimal morphological myeloid maturation. Dysplastic micromegakaryocytes and bone marrow fibrosis were observed predominantly in CMPD cases. RT-PCR followed by DNA sequencing showed that the AML1-/MDS1-/EVI1 (AME) fusion transcript was detected in all 5 cases assessed. Among the patients with CMPD, 8 died of disease (at a median of 6.5 mos) and 5 achieved disease remission with bone marrow transplantation. Among patients with acute myeloid leukemia/myelodysplastic syndrome, 7 died of disease (at a median of 2 mos) and 2 had persistent leukemia with short follow-up. CONCLUSIONS: Activation of AME through t(3;21) defines a highly aggressive, therapy-related leukemic blast syndrome. Prior treatment with hydroxyurea or other antimetabolites is implicated as a contributory cause.

Adult↗
PubMed2006

Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia: a report of POG study 9296.

PURPOSE: A previous Pediatric Oncology Group (POG) study showed high incidence of secondary acute myelogenous leukemia (AML) in children treated for T-cell acute lymphoblastic leukemia (T-ALL) or higher-stage lymphoblastic lymphoma. To prevent secondary neoplasms, induce prolonged asparagine depletion, and maintain high event-free survival (EFS) in children with newly diagnosed T-ALL or higher-stage non-Hodgkins lymphoma (NHL), we designed this pilot study to determine feasibility and safety of substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase. PATIENTS AND METHODS: Forty-five patients were entered, 29 with T-ALL and 16 with higher-stage NHL. Forty-two of 45 patients achieved complete remission (CR), and 27 completed the therapy in continuous CR. Treatment consisted of 4-week induction then 6 weeks consolidation and ten 9-week maintenance cycles. Therapy primarily comprised antimetabolites, anthracyclines, alkylating agents, and asparaginase. Expected chemotherapy duration was 100 weeks. RESULTS: Forty-two of 45 patients achieved CR, and 27 completed therapy. The most common toxicities were Grade 3 or 4 myelosuppression after cyclophosphamide/cytarabine and allergic reactions to asparaginase. Two died of sepsis early in maintenance. Five-year EFS was 68.5% (SE 9.1%) for T-ALL and 81.3% (SE 9.8%) for NHL. Five-year EFS was 73.1% (SE 6.8%) for the entire cohort. No patients treated entirely on this study developed secondary neoplasms. One patient taken off study for asparaginase toxicity was treated with multiagent therapy that contained teniposide, and died from secondary myelodysplasia (sMDS)/AML. CONCLUSION: Substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase in a dose-intensive regimen was feasible in children and young adults with newly diagnosed T-ALL or higher-stage NHL. EFS was not compromised and secondary neoplasms were decreased.

Adolescent↗