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  • 1
    Electronic Resource
    Electronic Resource
    A Three Dimensional Model of Human Thiopurine Methyltransferase; Ligand Interactions and Structural Consequences of Naturally Occurring Mutations (1998)
    Springer
    Journal of molecular modeling 4 (1998), S. 211-220 
    Details
    ISSN: 0948-5023
    Keywords: Keywords Thiopurine methyltransferase ; Homology model ; Mutations ; Ligand interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The three-dimensional model of human thiopurine methyltransferase (hTPMT) was constructed by molecular modeling. A multiple alignment of AdoMet dependent methyltransferases based on a structural superposition of the AdoMet binding domain of Hhai, TaqI and rCOMT was used in the modeling procedure. The reliability of the model was examined by comparing its conformation and packing properties with those of Hhai, TaqI and rCOMT and structures in the PDB-database. The examined criteria indicated a reliable model structure. The model gave insight into the structural effects of naturally occurring mutations of the hTPMT allele, and was used to characterize the ligand interactions of the protein. The residues Gln42 and Glu91 were predicted to participate in AdoMet binding through H-bond interactions whereas Phe146 participates through Van der Waal interaction. The cationic methyl-sulphonium group of AdoMet was located close to the aromatic residue Phe40. The model also indicated that substrates interact with hTPMT situated in a pocket consisting of the hydrophobic residues Phe40, Met148, Val184, Val220 and the charged residues Lys145, Glu218, Lys219. These residues were also included in a predictive explanation for the inhibitor/substrate preference of the enzyme. The most frequent of naturally occurring mutations was predicted to cause alterations on the surface of the protein with minor/none structural consequences. The mutation Ala80-Pro seemed directly to cause an inactive enzyme by disrupting the structure of the binding site of AdoMet.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s008940050078
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  • 2
    Electronic Resource
    Electronic Resource
    Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 119-124 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 μM, and concentrations of 7-OH-MTX declined triphasically, showing a t 1/2α value of 2.45 min, a t 1/2β value of 30.5 min, and a terminal half-life (t 1/2γ) of 240 min. The total clearance value was 14.5 ml min–1 kg, and the postdistributional volume of distribution (Vβ) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on kidney and liver cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685928
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  • 3
    Electronic Resource
    Electronic Resource
    Interactions of vinblastine and vincristine with methotrexate transport in isolated rat hepatocytes (1993)
    Springer
    Cancer chemotherapy and pharmacology 32 (1993), S. 209-214 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The accumulation of methotrexate (MTX) in the presence of vinblastine (VBL) and vincristine (VCR) was studied in isolated rat hepatocytes. In accordance with our recent study on vindesine (VDS), we found VBL and VCR to reduce net MTX accumulation significantly at 15 min after MTX addition. Drug concentrations of 100 μM VBL and 500 μM VCR led to 67% and 82% reductions in intracellular MTX, respectively. Since there was only a slight inhibition of MTX efflux by 100 μM VBL, the accumulation data demonstrate that the major effect of VBL is on MTX influx. Dixon-plot analyses are suggestive of competitive inhibition of the MTX influx, yielding inhibition constants (K i values) of 55 μM for VBL and 110 μM for VCR. Since theK i values correspond grossly to plasma levels obtained in humans shortly after the infusion of therapeutic doses of the vinca alkaloids studied herein, the interaction with MTX uptake could serve to diminish the toxicity of MTX to nonmalignant cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685837
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  • 4
    Electronic Resource
    Electronic Resource
    Inhibition of 7-hydroxymethotrexate formation by amsacrine (1991)
    Springer
    Cancer chemotherapy and pharmacology 28 (1991), S. 377-383 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The inhibition of methotrexate (MTX) biotransformation to 7-hydroxymethotrexate (7-OH-MTX) by 4′-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA) was studied in bile-drained rats in vivo and in incubates of isolated rat hepatocytes and rat-liver homogenate in vitro. In vivo, i.v. administration of 10 mg/kg mAMSA prior to [3H]-MTX infusion (50 mg/kg) led to a significant alteration in 7-OH-MTX kinetics. 7-OH-MTX peak concentrations and AUC in bile and serum were reduced by 75% and the recovery of MTX as 7-OH-MTX in bile and urine decreased by 70%, whereas MTX pharmacokinetics remained unaltered. In suspensions of isolated hepatocytes. 10 μm mAMSA led to a 54% decrease in 7-OH-MTX formation. However, the hepatocellular influx and efflux of MTX was not perturbed by mAMSA. Preincubation of rat-liver homogenates with 1.25–10 μm mAMSA reduced the formation of 7-OH-MTX by up to 73%. mAMSA appeared to inhibit MTX hydroxylation competitively, exhibiting aK iof 3 μm. Due to its inhibition of the MTX-oxidizing system, mAMSA may be beneficial in combination chemotherapy with MTX by reducing 7-OH-MTX-associated toxicity and, possibly, enhancing the cytotoxic effects of MTX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685693
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  • 5
    Electronic Resource
    Electronic Resource
    Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 119-124 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 μM, and concentrations of 7-OH-MTX declined triphasically, showing at1/2α value of 2.45 min, at1/2β value of 30.5 min, and a terminal half-life (t1/2γ) of 240 min. The total clearance value was 14.5 ml min−1 kg, and the postdistributional volume of distribution (Vβ) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on kidney and liver cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685928
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  • 6
    Electronic Resource
    Electronic Resource
    Maximum tolerated doses of methotrexate and 7-hydroxy-methotrexate in a model of acute toxicity in rats (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 69-73 
    Details
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxymethotrexate ; Methotrexate ; Maximum tolerated dose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD50 for reasons of animal welfare. Methods: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8–11.3 g/kg MTX and 0.1–1.2 g/kg 7-OH-MTX. Results: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. Conclusions: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800000111
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  • 7
    Electronic Resource
    Electronic Resource
    Methotrexate increases red blood cell concentrations of 6-methylmercaptopurine ribonucleotide in rats in vivo (1997)
    Springer
    Cancer chemotherapy and pharmacology 40 (1997), S. 367-370 
    Details
    ISSN: 1432-0843
    Keywords: Key words Methylmercaptopurine  ;  6-Thioguanine nucleotide  ;  Interaction  ;  Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To elucidate the effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism in rats. Methods: Fourteen rats were given 6-MP 20 mg/kg daily for 7 days. Seven of the rats were also given MTX 20 mg/kg on days 5 and 7. Blood samples were obtained from all rats on days 0, 5 and 8, and red blood cell (RBC) lysates were analysed for thiopurine methyltransferase (TPMT) activity and the concentration of methylated 6-MP metabolites [methyl mercaptopurine ribonucleotides (MMPRP)] and 6-thioguanine nucleotides (6-TGN). Results: The concentration of MMPRP increased 2.4 times from day 5 to day 8 in RBCs from rats given MTX in addition to 6-MP, as against 1.2 times in rats given 6-MP alone (P = 0.003). 6-TGN levels increased and TPMT activity decreased from day 5 to day 8, with no difference between the 6-MP and the 6-MP plus MTX groups. Conclusions: Single bolus doses of MTX increase the concentration of MMPRP in rats given daily s.c. doses of 6-MP, with no effect on 6-TGN concentration or TPMT activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050672
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