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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nuclear medicine 23 (1996), S. 568-570 
    ISSN: 1619-7089
    Keywords: Technetium-99m sestamibi ; Multidrug resistance ; P-glycoprotein ; Glutathione
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An in vitro study was designed to evaluate the uptake of sestamibi (MIBI) in P-glycoprotein (Pgp) and glutathione-associated (GSH) multidrug-resistant (MDR) cell lines. MIBI uptake was studied in various human breast carcinoma cell lines, i.e. in wild-type (MCF7/wt) cells, in adriamycin-resistant (MCF7/adr) cells which express Pgp and in melphalan-resistant (MCF7/mph) cells with increased levels of GSH. The effects of buthiomine sulphoximine (BSO) and verapamil on MIBI uptake were also studied in the MCF7/mph and MCF7/adr cells respectively. The cells were incubated for 1 h with a dose of 0.1 MBq thallium-201 and technetium-99m MIBI. Both MIBI and201Tl uptakes were higher for MCF7/mph cells than for the other cells studied. The mean MIBI uptake in MCF7/adr cells was significantly lower than that in MCF7/wt cells (1.9%±0.5% vs 3.1%.0.6%;P 〈0.01). Verapamil treatment increased the MIBI uptake in MCF7/adr cells (to 2.6%.0.3%;P 〈0.05). Treatment of MCF7/mph cells with BSO resulted in a significant reduction in GSH content (from 243.2±81.1 nmoUmg protein to 17.6±4.4 nmol/mg protein;P 〈0.001). However, MIBI uptake in BSO-treated and untreated MCF7/mph cells was similar (4.43%±0.5% and 5.93%±1.7%, respectively;P 〉0.1). This study suggests that the uptake of MIBI is not diminished by glutathione-associated drug resistance and that MIBI uptake in a tumour sample does not necessarily indicate that a cancer is sensitive to drugs.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 40 (1997), S. 409-414 
    ISSN: 1432-0843
    Keywords: Key words Busulfan ; Glioblastoma multiforme ; Xenograft ; Drug resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Busulfan is an alkylating agent commonly used in the treatment of chronic myelogenous leukemia and in combination with cyclophosphamide in preparation for allogeneic bone marrow transplantation. Serial treatment of a childhood high-grade glioma xenograft (D-456 MG) with busulfan resulted in a busulfan-resistant xenograft, D-456 MG(BR). Cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea was seen but not resistance to cyclophosphamide or CPT-11. Cytoplasmic levels of glutathione in D-456 MG(BR) were approximately one-half those found in D-456 MG. This depletion could not be explained by levels of glutathione-S-transferase, or by amplification, rearrangement, or increased levels of transcript of γ-glutamylcysteine synthetase. Furthermore, depletion of glutathione in D-456 MG did not alter busulfan activity. Quantitation of busulfan levels in D-456 MG and D-456 MG(BR) xenografts following treatment of mice at the dose lethal to 10% of the animals demonstrated that significantly lower levels of drug were achieved in D-456 MG(BR). These studies suggest that alterations in drug transport or metabolism of busulfan may play a role in the resistance of D-456 MG(BR) to this alkylator.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 379-384 
    ISSN: 1432-0843
    Keywords: Melphalan ; l-Amino acid oxidase ; Large neutral amino acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously shown that diet restriction-induced depletion of large neutral amino acids (LNAAs) in murine plasma to 46% of control significantly enhances intracranial delivery of melphalan without enhancing delivery to other organs. Studies have now been conducted to determine whether more substantial LNAA depletion could further enhance intracranial delivery of melphalan. Treatment with Lamino acid oxidase (LOX) significantly depleted murine plasma LNAAs: phenylalanine, leucine, and tyrosine (〉95%); methionine (83%); isoleucine (70%); and valine (46%). Experiments evaluating the intracellular uptake of melphalan and high-pressure liquid chromatography quantitation of melphalan metabolites revealed, however, that melphalan is rapidly degraded in the presence of LOX, and that the timing of the administration of melphalan following the use of LOX to deplete LNAAs is crucial. Conditions were found under which LOX-mediated degradation of melphalan was minimized and LNAA depletion was maximized, resulting in a potentiation of the antitumor effect of melphalan on human glioma xenografts in nude mice. Such potentiation could not be obtained using diet restriction alone.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Chichester : Wiley-Blackwell
    Biological Mass Spectrometry 8 (1981), S. 95-98 
    ISSN: 1052-9306
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: L-Methionine, L-methionine sulfone, L-methionine-SR-sulfoxide, L-methionine-SR-sulfoximine, DL-ethionine-SR-sulfoximine, DL-prothionine-SR-sulfoximine, DL-buthionine-SR-sulfoximine, α-methyl-DL-methionine-SR-sulfoximine, α-ethyl-DL-methionine-SR-sulfoximine and β-methyl-DL-methionine-SR-sulfoximine were subjected to chemical ionization mass spectral analysis using isobutane as reactant. The resulting fragmentation patterns are discussed in relation to differences in structural and chemical properties. It was found that the sulfoximines exhibit chemical ionization mass spectra that are unique among amino acids.
    Additional Material: 1 Tab.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of medicinal chemistry 37 (1994), S. 885-887 
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of medicinal chemistry 36 (1993), S. 491-496 
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 379-384 
    ISSN: 1432-0843
    Keywords: Key words Melphalan ; L-Amino acid oxidase ; Large neutral amino acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We have previously shown that diet restriction-induced depletion of large neutral amino acids (LNAAs) in murine plasma to 46% of control significantly enhances intracranial delivery of melphalan without enhancing delivery to other organs. Studies have now been conducted to determine whether more substantial LNAA depletion could further enhance intracranial delivery of melphalan. Treatment with L-amino acid oxidase (LOX) significantly depleted murine plasma LNAAs: phenylalanine, leucine, and tyrosine (〉95%); methionine (83%); isoleucine (70%); and valine (46%). Experiments evaluating the intracellular uptake of melphalan and high-pressure liquid chromatography quantitation of melphalan metabolites revealed, however, that melphalan is rapidly degraded in the presence of LOX, and that the timing of the administration of melphalan following the use of LOX to deplete LNAAs is crucial. Conditions were found under which LOX-mediated degradation of melphalan was minimized and LNAA depletion was maximized, resulting in a potentiation of the antitumor effect of melphalan on human glioma xenografts in nude mice. Such potentiation could not be obtained using diet restriction alone.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 39 (1996), S. 179-186 
    ISSN: 1432-0843
    Keywords: Key words Melphalan ; L-Amino acid oxidase ; Large neutral amino acids ; Glioma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  These studies evaluated the efficacy of sequential pretreatment with L-amino acid oxidase (LOX) and LOX antiserum in the modulation of melphalan activity against intracranial glioma in athymic nude mice. LOX produced statistically significant (P〈0.01) depletion of the large neutral amino acids isoleucine, leucine, methionine, phenylalanine, tyrosine, and valine in murine plasma at doses of 100 and 200 μg administered intravenously. Polyclonal anti-LOX antibody was successfully produced in mice, rabbits, and goats subsequent to immunization with LOX. Staphylococcal protein A-purified rabbit anti-LOX serum inhibited approximately 50% of LOX activity in vitro relative to control samples. This antiserum was used in vivo to inactivate LOX after it had depleted the large neutral amino acids, thereby preventing LOX-mediated catabolism of melphalan. Inoculation of three mice with rabbit anti-LOX serum after the treatment with LOX (100 μg) reduced LOX activity by 100%, 89%, and 100% at 6 h compared with reductions of 80%, 59%, and 52% over the same period in animals receiving LOX alone. In three separate studies using groups of eight to ten mice bearing intracranial human glioma xenografts, pretreatment with LOX followed by anti-LOX serum increased the antitumor activity of melphalan as compared with treatments with melphalan plus LOX, melphalan plus anti-LOX serum, or melphalan alone.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 28 (1991), S. 15-21 
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Melphalan-induced toxicity in nude mice following pretreatment with a regimen ofL-buthionine sulfoximine (BSO), previously shown to enhance the activity of this alkylating agent against rhabdomyosarcoma and glioma xenografts, was examined. Mice were pretreated with i.p. BSO (2.5 mmol/kg×7 doses at 12-h intervals plus concomitant availability of a 20-mm solution in the drinking water) or vehicle prior to a single i.p. injection of melphalan (35.65 mg/m2). As compared with control animals who received no BSO pretreatment, mice pretreated with BSO lost weight prior to therapy with melphalan (6.9% weight loss vs 0.3% weight gain;P〈0.005) and showed a greater mean nadir weight loss after melphalan (3.8% vs 2.1%;P=0.049). Treatment with melphalan was associated with histologic evidence of reversible gastrointestinal toxicity, reversible myelosup-pression, and histologic evidence of acute renal tubular necrosis, with no differences being observed between mice that had been pretreated with BSO and those that had been pretreated with vehicle. No evidence of cardiac, hepatic, or skeletal muscle toxicity was found in melphalan-treated animals. These results suggest that treatment of nude mice with melphalan following BSO-mediated depletion of glutathione does not result in enhanced organ toxicity despite an increase in the antineoplastic activity of this alkylating agent.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 31 (1993), S. 376-380 
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The tolerated dose of melphalan is limited by bone marrow suppression; when this complication is ameliorated by bone marrow transplantation, the dose-limiting toxicity becomes gastrointestinal mucositis. No intervention to date has been successful in modulating this lifethreatening complication of melphalan. We conducted studies to develop a murine model of melphalan-induced gastrointestinal toxicity to facilitate the preclinical identification of effective strategies for reducing this toxicity. Melphalan given at the 90% lethal dosage produced severe gastrointestinal mucositis and mortality (13 of 23 treated mice). Syngeneic bone marrow transplantation, effective in preventing the myeloablation produced by total-body irradiation, was ineffective in preventing melphalan-induced mortality (16 of 23 treated mice), indicating that gastrointestinal mucositis was the dose-limiting toxicity. On the basis of the results of previous studies, which revealed that depletion of glutathione enhances the antineoplastic activity of melphalan and that glutathione is required for murine intestinal function, we attempted to modulate melphalan-induced gastrointestinal toxicity by the administration of glutathione (8–10 mmol/kg given in 1 ml sterile water by gavage at 12-h intervals for 4–8 doses). Glutathione therapy failed to produce a significant increase in mucosal glutathione content in animals treated with melphalan plus glutathione gavage as compared with those receiving melphalan alone (P〉0.05), and histologic mucosal injury secondary to melphalan was not reduced. The administration of glutathione in the presence or absence of concomitant bone marrow transplantation did not decrease melphalan-induced mortality (melphalan alone, 16/26 deaths; melphalan plus glutathione, 14/25 deaths; melphalan plus glutathione plus bone marrow transplantation, 20/26 deaths). Studies using a reduced melphalan dose (50% lethal dosage) produced similar results, with no survival benefit being seen following glutathione administration. Our studies suggest that melphalan-induced mucositis can be studied in a mouse model in which this complication is doselimiting. Although glutathione administration at the dose and schedules initially studied is not effective in reducing this damage, other therapeutic strategies such as the use of alternative glutathione regimens or other thiols can be effectively studied in this system.
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