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  • 1
    Electronic Resource
    Electronic Resource
    Cytotoxicity, DNA cross-linking, and DNA single-strand breaks induced by cyclophosphamide in a rat leukemia in vivo (1993)
    Springer
    Cancer chemotherapy and pharmacology 31 (1993), S. 381-386 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A study of cyclophosphamide (CP)-induced DNA damage and repair occurring in vivo was conducted in the brown Norway rat myelocytic leukemia (BNML) model. DNA single-strand breaks (SSB), DNA-DNA interstrand cross-links (DIC), DNA-protein cross-links (DPC), and DNA double-strand breaks (DSB) were measured by alkaline and neutral elution. After i. p. injection of 50 mg/kg CP, DIC were detectable at 1 h and peaked at 8 h. DPC were detectable at 2 h and peaked at 6 h. Both DIC and DPC persisted at a relatively high level until 28 h. Dose-response curves for both DIC and DPC were determined at 4 h after CP injection over the dose range of 25–150 mg/kg. These doses ranged from the minimally effective dose to doses curative for rats bearing this leukemia (1- to 9-log kill of leukemia cells). No SSB or DSB was observed at 4 h after CP injection over the dose range of 15–250 mg/kg, but a low level of SSB was observed at 18–28 h after CP treatment. These data suggest that the cytotoxic effect of CP in vivo is mediated mostly by DIC and DPC. SSB appearing late after CP injection in vivo may be a reflection of repair of DIC and DPC and an indication of the optimal timing for administration of DNA-repair inhibitors. This observation is of interest since our earlier work demonstrated that hydroxyurea can potentiate the therapeutic benefit of CP in this model when it is given over the 4-day period immediately after CP treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686152
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  • 2
    Electronic Resource
    Electronic Resource
    A phase I trial of high-dose continuous-infusion hydroxyurea (1993)
    Springer
    Cancer chemotherapy and pharmacology 33 (1993), S. 139-143 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated, doses (MTD) of intravenous hydroxyurea given as a 24-or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m2 following a bolus of 1,690 mg/m2, and the mean (±SD) plasma steady-state concentration was 1.93±0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m2 following a bolus of 2,197 mg/m2 and the mean steady-state level was 1.43±0.31 mM. The doselimiting toxicity on both schedules was marrow suppression manifesting as, neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685331
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  • 3
    Electronic Resource
    Electronic Resource
    Hydroxyurea potentiation of the antineoplastic activity of cyclophosphamide and 4′-(9-acridinylamino)methanesulfon-M-anisidide (AMSA) in the brown Norway rat myelocytic leukemia model (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 26-30 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The activities of hydroxyurea (HU), 4′-(9-acridinylamino) methanesulfon-M-anisidide (AMSA) and cyclophosphamide (CY) were examined in the brown Norway rat myelocytic leukemia model in experiments designed to determine the synergy, optimal drug sequencing, and therapeutic index of combinations of these agents. A single dose of CY or four consecutive daily doses of AMSA produced increased survival in leukemic rats, with a positive-slope dose-response curve up to the maximum tolerated dose (MTD). HU at 1/2 MTD produced a minimal antileukemic effect but significantly potentiated the antineoplastic activity of 1/2 MTD of CY or AMSA with no significant toxic death rate. Drug-sequence experiments demonstrated that maximal synergy was achieved when HU was given immediately after CY but immediately before or during AMSA administration. No significant cure rate was seen with any CY/HU or HU/AMSA sequence. The three drugs given in the sequence of CY followed 3 days later by HU and AMSA simultaneously, however, was curative in the majority of rats with advanced leukemia, whereas other sequences were more toxic or less effective. Each of the drugs in these experiments was given at 1/2 of its single-agent MTD. HU significantly potentiates the antineoplastic effect of CY and AMSA in a drug-sequence-dependent manner in this model, apparently with an improved therapeutic index.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00258453
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  • 4
    Electronic Resource
    Electronic Resource
    Factors affecting plasma postheparin diamine oxidase activity (1991)
    Springer
    Digestive diseases and sciences 36 (1991), S. 1582-1588 
    Details
    ISSN: 1573-2568
    Keywords: Crohn's disease ; diamine oxidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma postheparin diamine oxidase (DAO) activity has been evaluated for assessing disease activity in Crohn's disease (CD) and other intestinal disorders. Since the mechanism of the reduced plasma DAO activity is poorly understood, our aim was to determine the effect of extent and location of disease and prior resection and therapy on plasma DAO activity in Crohn's disease. Plasma postheparin DAO activity was significantly lower (17.4±3.0 vs 32.8±30.8 units/ml) and Crohn's disease activity index (178±105 vs 14±19,P〈0.05) (CDAI) higher in 37 patients with CD compared to 30 normal volunteers. There was no overall correlation between DAO activity and CDAI. Effective medical or surgical therapy increased DAO activity and decreased CDAI, while clinical recurrence had the opposite effect. DAO activity was not related to the extent of small bowel disease (13.2±9.1; 〈30 cm, 18.5±11.8; 30–60 cm, and 5.7±6.4 units/ml; 〉60 cm) or colonic disease (13.0±6.9 segmental vs 24.0±15.4 units/ml, pancolitis). DAO activity was similar with small or large bowel disease (14.3±10.6 vs 18.8±13.1 units/ml). Prior enterectomy or colectomy did not significantly influence DAO activity. DAO activity responds predictably after effective therapy and recurrence and may prove useful in monitoring individual patients with CD. Failure of extent and location of disease and prior resection to influence DAO activity suggests that DAO activity is not directly related to enterocyte mass.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01296401
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    Paper (German National Licenses)
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