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  • 1
    Electronic Resource
    Electronic Resource
    Treatment of Central Nervous System Xenografts with Camptothecins (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 803 (1996), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1996.tb26390.x
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  • 2
    Electronic Resource
    Electronic Resource
    Treatment of subcutaneous and intracranial brain tumor xenografts withO 6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (1993)
    Springer
    Cancer chemotherapy and pharmacology 32 (1993), S. 471-476 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract O 6-Alkylguanine-DNA alkyltransferase (AT) is a cellular protein that protects cells from the cytotoxic effects of nitrosoureas by repairing alkyl lesions at theO 6 position of guanine. We have studied the ability ofO 6-benzylguanine to deplete AT activity in brain tumor xenografts and thereby increase the sensitivity of these tumors to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In toxicity studies, pretreatment of athymic mice withO 6-benzylguanine increased the toxicity of BCNU significantly. After i.p. injection ofO 6-benzylguanine into athymic mice carrying subcutaneous (s. c.) D341MED, a human medulloblastoma xenograft with a high AT activity, the AT activity of the tumors became undetectable within 1 h and remained depleted until 36 h. In s. c. xenografts to D341MED, treatment withO 6-benzylguanine followed 1 h later by BCNU produced a significantly greater growth delay (14.8 days) than was seen with BCNU alone (2.3 days). A lower pretreatment dose ofO 6-benzylguanine produced a significantly smaller therapeutic effect. Delaying the administration of BCNU until 36 h afterO 6-benzylguanine resulted in a growth delay (1.2 days) that was not significantly different from that produced by the control or BCNU alone. In athymic mice with intracranial (i.c.) xenografts of D341MED, pretreatment withO 6-benzylguanine followed 1 h later by BCNU produced a significantly increased survival as compared with that of the control, BCNU alone,O 6-benzylguanine alone, andO 6-benzylguanine followed 36 h later by BCNU. In experiments with s.c. xenografts of D245MG, a human glioma xenograft with undetectable AT activity, pretreatment withO 6-benzylguanine 1 h prior to BCNU produced a significantly greater effect than was seen with BCNU treatment alone. The combination regimen, however, was not as effective as an equitoxic dose of BCNU alone. These studies suggest thatO 6-benzylguanine may be a useful adjuvant to nitrosourea therapy in human malignancies that exhibit a range of AT activities and that dose and timing are important variables in achieving therapeutic success. These data also indicate that therapeutic potentiation of BCNU byO 6-benzylguanine can be achieved in i.c. tumors. As a result, this approach may be useful in the treatment of neoplasms of the central nervous system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685892
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  • 3
    Electronic Resource
    Electronic Resource
    Phase I study of BCNU and intravenous 6-mercaptopurine in patients with anaplastic gliomas (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 272-276 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary On the basis of response rates of up to 50%, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] is the primary drug used in the chemotherapy of anaplastic gliomas. Preclinical data obtained in several experimental systems show that the cytotoxicity of chloroethylnitrosoureas can be increased by the concomitant use of thiopurines. In this phase I trial, patients with anaplastic gliomas received standard-dose BCNU (200 mg/m2×1) in combination with escalating doses of intravenous 6-mercaptopurine (200, 350, 500, and 750 mg/m2 daily×3), with BCNU being given on day 3 to maximize the effect of the drugs on cellular DNA. No increase in hematologic toxicity was demonstrated as the dose of 6-mercaptopurine was increased. Responses and stabilization of disease were observed in several patients. Due to the safety of and the evidence of activity found for this regimen in the present trial, 750 mg/m2 6-mercaptopurine has been incorporated into subsequent studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686294
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  • 4
    Electronic Resource
    Electronic Resource
    Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 171-174 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The activity of dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts derived from ependymomas (D528 EP, D612 EP), childhood high-grade gliomas (D-456 MG, D-212 MG), adult high-grade gliomas (D-245 MG, D-54 MG), and medulloblastomas (D425 Med) growing s.c. and i.c. (intracranially) in athymic nude mice. Topotecan was given at a dose of 1.9 mg/kg by i.p. injection in 0.9% saline using a volume of 90 ml/m2 on days 1–5 and 8–12, which represents the dose lethal to 10% of treated animals. Topotecan was active in the therapy of all s.c. xenografts tested, with growth delays ranging from 6.3 days in D-54 MG to 55.7 days in D528 EP. Topotecan produced statistically significant tumor regressions in D425 Med, D-456 MG, D-245 MG, D528 EP, and D612 EP. No tumor regression was seen in any control animal. Statistically significant increases in median survival were seen in the two i.c. xenografts — D-456 MG (28.6% increase) and D-54 MG (39% increase) —treated with topotecan. These studies suggest that topotecan may be an important new addition to the therapy of central nervous system tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685936
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  • 5
    Electronic Resource
    Electronic Resource
    The effect of L-amino acid oxidase on activity of melphalan against an intracranial xenograft (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 379-384 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00686186
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  • 6
    Electronic Resource
    Electronic Resource
    The effect ofl-amino acid oxidase on activity of melphalan against an intracranial xenograft (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 379-384 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00686186
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  • 7
    Electronic Resource
    Electronic Resource
    Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 479-482 
    Details
    ISSN: 1432-0843
    Keywords: Key words Vinorelbine ; Vinca alkaloid ; CNS tumors Xenografts ; Mismatch repair
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The activity of vinorellbine, a new semisynthetic vinca alkaloid, was evaluated against a battery of human tumor xenografts derived from adult and pediatric CNS malignancies. Methods: Tumors included adult high-grade gliomas (D-54 MG, D-245 MG), childhood high-grade gliomas (D-212 MG, D-456 MG), medulloblastomas (D-341 MED, D-487 MED), ependymomas (D-612 EP, D-528 EP), and a mismatch repair-deficient procarbazine-resistant glioma [D-245 MG (PR)]. Tumors were grown subcutaneously in athymic nude mice and vinorelbine was administered at a dose of 11 mg/kg on days 1, 5, and 9. Additionally, vinorelbine was also administered in combination with BCNU against D-54 MG. Results: Vinorelbine produced statistically significant growth delays in D-456 MG, D-245 MG, and D-245 MG (PR). No statistically significant growth delays were observed in D-54 MG, D-487 MED, D-212 MG, D-528 EP, D-341 MED or D-612 EP. The antitumor effects of the vinorelbine/BCNU combination were additive. Growth delays observed in the procarbazine-resistant line [D-245 MG (PR)] were greater than twofold the delays seen in the parent line (D-245 MG). Vincristine was equally potent against D-245 MG and D-245 MG (PR). Taxol demonstrated little activity against D-245 MG but produced 32- and 18-day growth delays in D245 MG (PR). Conclusions: These studies indicate that vinorelbine possesses antitumor activity against several glioma tumor xenografts with marked activity in a mismatch repair deficient-tumor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050848
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  • 8
    Electronic Resource
    Electronic Resource
    Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents (1998)
    Springer
    Cancer chemotherapy and pharmacology 41 (1998), S. 485-490 
    Details
    ISSN: 1432-0843
    Keywords: Key words Irinotecan (CPT-11) ; Alkylators ; Glioma ; Medulloblastoma ; Ependymoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two major obstacles in the treatment of patients with central nervous system malignancies are drug resistance and host toxicity. The goal of combination chemotherapy is to achieve therapeutic effects that are more favorable than using a single drug alone, but without an increase in normal organ toxicity. The study reported here examined the combination of a topoisomerase I inhibitor, irinotecan (CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide. We evaluated the antitumor effects of these three combinations against a panel of human tumor xenografts derived from central nervous system malignancies, including adult high-grade gliomas (D-54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments, the alkylating agents were given on day 1 in doses varying from 10% to 75% of the dose lethal to 10% of the animals, and CPT-11 was given on days 1–5 and 8–12 in doses varying from 10% to 100% of the dose lethal to 10% of the animals. The antitumor effects of the various combinations ranged from less than additive (7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to statistically significant (P 〈 0.001) supraadditive effects (18.80 days above additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG). These studies show that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antitumor effect in some cases well above additive with no increase in host toxicity (0/10 deaths in both experiments cited above) and should be considered for combination chemotherapy of central nervous system malignancies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050771
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  • 9
    Electronic Resource
    Electronic Resource
    Melphalan-induced toxicity in nude mice following pretreatment with buthionine sulfoximine (1991)
    Springer
    Cancer chemotherapy and pharmacology 28 (1991), S. 15-21 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00684950
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  • 10
    Electronic Resource
    Electronic Resource
    Development of a model of melphalan-induced gastrointestinal toxicity in mice (1993)
    Springer
    Cancer chemotherapy and pharmacology 31 (1993), S. 376-380 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686151
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