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Kurt A Jaeckle - One of the best experts on this subject based on the ideXlab platform.
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phase iii randomized study of postradiotherapy chemotherapy with α difluoromethylornithine procarbazine n 2 chloroethyl n cyclohexyl n nitrosurea vincristine dfmo pcv versus pcv for glioblastoma multiforme
Clinical Cancer Research, 2000Co-Authors: Victor A Levin, Kurt A Jaeckle, Joon H Uhm, A Choucair, Patrick J Flynn, W Alfred K Yung, Michael D Prados, Janet M Bruner, Susan M Chang, Athanassios P KyritsisAbstract:Although the efficacy of the Nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a Nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the Nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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correlation of tumor o6 methylguanine dna methyltransferase levels with survival of malignant astrocytoma patients treated with bis chloroethylNitrosourea a southwest oncology group study
Journal of Clinical Oncology, 1998Co-Authors: Kurt A Jaeckle, H J Eyre, Jeannette J Townsend, S Schulman, H M Knudson, Michael Belanich, D B Yarosh, S I Bearman, D J Giroux, S C ScholdAbstract:PURPOSEPrior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to Nitrosoureas. The observed Nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas.PATIENTS AND METHODSWe correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylNitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival.RESULTSOf 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overal...
Stanton L Gerson - One of the best experts on this subject based on the ideXlab platform.
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retroviral transduction of a mutant methylguanine dna methyltransferase gene into human cd34 cells confers resistance to o6 benzylguanine plus 1 3 bis 2 chloroethyl 1 Nitrosourea
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Jane S Reese, James A Allay, Omer N Koc, Lili Liu, Keun Myoung Lee, Weldon P Phillips, Stanton L GersonAbstract:Human CD34 cells express low levels of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and are sensitive to 1,3-bis(2-chloroethyl)-1-Nitrosourea (BCNU). Gene transfer of the AGT gene, methylguanine DNA methyltransferase (MGMT), results in only modest BCNU resistance. Recently, an AGT inhibitor, O6-benzylguanine (BG), entered clinical trials. In preclinical studies, BG potentiated the cytotoxic effect of BCNU in tumors but increased toxicity to normal CD34 cells. We transferred a mutant MGMT containing a glycine-to-alanine mutation at position 156, resulting in marked resistance to BG, into Chinese hamster cells; the K562 cell line and human CD34 cells used the retroviral backbone MFG. In each instance, cells expressed increased AGT and were much more resistant to the combination of BG and BCNU than the parental cells or cells transduced with wild-type MGMT. Furthermore, the transduction efficiency in human CD34 cells was in excess of 70%, and the proportion of CD34 transduced cells resistant to the combination was >30%. Thus, retroviral-mediated transduction of a mutant MGMT into CD34 cells appears to be an effective way to induce selective resistance to a drug combination designed to overcome a significant resistance mechanism to Nitrosoureas in tumors.
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retroviral transduction and expression of the human alkyltransferase cdna provides Nitrosourea resistance to hematopoietic cells
Blood, 1995Co-Authors: James A Allay, Luba L Dumenco, Omer N Koc, Lili Liu, Stanton L GersonAbstract:Myelosuppression is the dose-limiting toxicity for Nitrosourea chemotherapy. This toxicity predominantly involves modification of the O6 position of guanine with an alkyl moiety. The enzyme responsible for repair of O6-alkylguanine adducts, O6-alkylguanine-DNA alkyltransferase (alkyltransferase), is expressed at low levels in bone marrow (BM) cells. High alkyltransferase expression prevents the cytotoxicity and carcinogenicity of Nitrosoureas in several transgenic and in vitro gene transfer models. We used gene transfer using a novel myeloproliferative sarcoma virus (MPSV) based retrovirus (vM5MGMT) to express the human alkyltransferase cDNA (MGMT) in human and murine hematopoietic cells. Transduced K562 cells had very high levels of alkyltransferase expression and significantly increased resistance to 1,3-bis (2-chloroethyl) Nitrosourea (BCNU) as compared with untransduced K562 cells. Primary murine BM progenitors showed a high transduction efficiency with vM5MGMT and have increased BCNU resistance in vitro. After BM transplantation with vM5MGMT-transduced BM cells and BCNU treatment of these mice, BM, spleen and thymus had a 10- to 40-fold increase in alkyltransferase expression that persisted for at least 23 weeks posttransplantation. Progenitor cells procured from mice expressing high levels of alkyltransferase also had increased resistance to BCNU. Thus, an MPSV-based retroviral vector transduces mouse and human hematopoietic cells at high efficiency and results in high levels of gene expression both in vitro and in vivo. Overexpression of the alkyltransferase protein may protect hematopoietic progenitors from Nitrosourea-induced myelosuppression.
John K Park - One of the best experts on this subject based on the ideXlab platform.
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Nitrosoureas inhibit the stathmin mediated migration and invasion of malignant glioma cells
Cancer Research, 2008Co-Authors: Xingjie Liang, Yong Choi, Dan L Sackett, John K ParkAbstract:Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of Nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal Nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-Nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that Nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.
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Nitrosoureas inhibit the stathmin mediated migration and invasion of malignant glioma cells
Cancer Research, 2008Co-Authors: Xingjie Liang, Yong Choi, Dan L Sackett, John K ParkAbstract:Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of Nitrosoureas on these cell movement–related processes. Scratch wound–healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal Nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-Nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μmol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that Nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects. [Cancer Res 2008;68(13):5267–72]
S C Schold - One of the best experts on this subject based on the ideXlab platform.
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correlation of tumor o6 methylguanine dna methyltransferase levels with survival of malignant astrocytoma patients treated with bis chloroethylNitrosourea a southwest oncology group study
Journal of Clinical Oncology, 1998Co-Authors: Kurt A Jaeckle, H J Eyre, Jeannette J Townsend, S Schulman, H M Knudson, Michael Belanich, D B Yarosh, S I Bearman, D J Giroux, S C ScholdAbstract:PURPOSEPrior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to Nitrosoureas. The observed Nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas.PATIENTS AND METHODSWe correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylNitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival.RESULTSOf 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overal...
Xingjie Liang - One of the best experts on this subject based on the ideXlab platform.
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Nitrosoureas inhibit the stathmin mediated migration and invasion of malignant glioma cells
Cancer Research, 2008Co-Authors: Xingjie Liang, Yong Choi, Dan L Sackett, John K ParkAbstract:Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of Nitrosoureas on these cell movement–related processes. Scratch wound–healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal Nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-Nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μmol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that Nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects. [Cancer Res 2008;68(13):5267–72]
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Nitrosoureas inhibit the stathmin mediated migration and invasion of malignant glioma cells
Cancer Research, 2008Co-Authors: Xingjie Liang, Yong Choi, Dan L Sackett, John K ParkAbstract:Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of Nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal Nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-Nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that Nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.
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the 1p encoded protein stathmin and resistance of malignant gliomas to Nitrosoureas
Journal of the National Cancer Institute, 2007Co-Authors: Tien Peng, Oluwaseun Akeju, Jean C Zenklusen, Xingjie Liang, Yuri Kotliarov, Howard A. Fine, Sandra Pastorino, Dragan Maric, Wei Zhang, Umberto De GirolamiAbstract:Background Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1 p (1p +/- ). Patients with 1p +/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-Nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1 p-encoded proteins in 1p +/- and 1p +/+ malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. Methods We used a comparative proteomic screen of A172 (1p +/- ) and U251 (1p +/+ ) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p +/- and 1p +/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with Nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Results Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [Cl] = 0 to 90 months), 17 months (95% Cl = 10.6 to 23.4 months), and 6 months (95% Cl = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of Nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin +/- tumors was 95 days (95% Cl = 68.7 to 121.3 days) and that of mice with stathmin +/+ tumors was 64 days (95% Cl = 58.2 to 69.8 days) (difference = 31 days, 95% Cl = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. Conclusions Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p +/- anaplastic oligodendroglioma tumors.