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  • 1
    Electronic Resource
    Electronic Resource
    Biochemical modulation of 5-fluorouracil with or without leucovorin by a low dose of brequinar in MGH-U1 cells (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 370-376 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Combination of low doses of de novo pyrimidine biosynthesis inhibitors with 5-fluorouracil (FU) has been proposed to increase the antitumor activity of FU. Brequinar is such an inhibitor that has little clinical antitumor effect when used alone. We determined the clonogenic survival of MGH-U1 cells treated with FU±leucovorin (LV)±brequinar and examined the effects of these treatments on thymidylate synthase (TS). After 24 h exposure, the concentrations resulting in 50% inhibition of cell growth (IC50) for brequinar, FU, and FU+LV (100 μm) were 0.4, 20, and 10 μm, respectively. Both 24 h pretreatment and 48 h continuous treatment with the IC10 (0.1 μm) of brequinar increased the cytotoxicity of FU but did not enhance that of FU+LV. Simultaneous 24 h exposure to 0.1 μm brequinar and FU±LV did not increase the cytotoxicity of FU±LV. Intracellular cytidine triphosphate (CTP) and uridine triphosphate (UTP) pools, free TS binding sites, and levels of free fluorodeoxyuridine monophosphate (FdUMP) and deoxyuridine monophosphate (dUMP) were measured in cells pretreated with 0.1 μm brequinar for 24 h alone or followed by a 2-h exposure to FU (25 μm)±LV (100 μm). In brequinar-treated cells, CTP and UTP pools amounted to 68% and 46% of control values, respectively. The free TS binding sites remaining amounted to 70% of control values in cells treated with FU and 9% of control levels in those treated with FU + brequinar. Free FdUMP levels increased 5-fold in cells pretreated with brequinar as compared with those treated with FU alone. The increased formation of FdUMP was inhibited by simultaneous exposure to 100 μm hypoxanthine and 25 μm FU. Intracellular dUMP levels were not affected by brequinar. We conclude that a low dose of brequinar increases the cytotoxicity of FU but does not enhance that of FU+LV when exposure to brequinar precedes FU treatment. This potentiation appears to be mediated by the increased formation of FdUMP as a consequence of an increase in the cosubstrate phosphoribosyl pyrophosphate (PRPP).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689965
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 493-496 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (〈65 or 〉65 years) versus dose delivered [〈 the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (〈 grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were 〉65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686507
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 493-496 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (〈65 or 〉65 years) versus dose delivered [〈 the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (〈 grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were 〉65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686507
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Forced secondary resonances at the 3 : 1 commensurability (1994)
    Springer
    Celestial mechanics and dynamical astronomy 59 (1994), S. 313-325 
    Details
    ISSN: 1572-9478
    Keywords: Forced secondary resonance ; degenerate Hamiltonian system ; stochastic web ; adiabatic approximation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract For the 3 : 1 Jovian resonance problem, the time scales of the two degrees of freedom of the resonant Hamiltonian are well-separated [5]. With the adiabatic approximation, the solution for the fast oscillations can be found in terms of the slowly varying variables. Thus the rapidly oscillating terms in the slow oscillation equations can be treated as forced terms. We refer to the resonance between the forcing and intrinsic frequencies as a forced secondary one in this paper. We discuss the forced secondary resonances in asteroidal motion at the 3 : 1 commensurability by using Wisdom's method. The results show that the orbits situated originally near the resonance will leave the neighbourhood of resonance and tend to the separatrices and critical points for different energies, respectively. We have not found any stochastic web as expected in this case. Moreover, we study the problem of validity on the approximation of a system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00692100
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    Paper (German National Licenses)
    Fulltext
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