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dc.contributor.authorChinnasamy, Nachimuthu
dc.contributor.authorRafferty, Joseph A
dc.contributor.authorLashford, Linda S
dc.contributor.authorChinnasamy, Dhanalakshmi
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorThatcher, Nick
dc.contributor.authorDexter, T Michael
dc.contributor.authorFairbairn, Leslie J
dc.date.accessioned2010-01-20T15:41:38Z
dc.date.available2010-01-20T15:41:38Z
dc.date.issued1999-11
dc.identifier.citationProtection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy. 1999, 13 (11):1776-83 Leukemiaen
dc.identifier.issn0887-6924
dc.identifier.pmid10557052
dc.identifier.urihttp://hdl.handle.net/10541/90155
dc.description.abstractThe effect of expression of an O6-benzylguanine (O6-beG)-resistant mutant (hATPA/GA) of human O6-alkylguanine-DNA alkyltransferase (ATase) on the in vivo toxicity and clastogenicity of the anti-tumour agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to murine bone marrow has been investigated. When compared with control animals, the bipotent granulocyte-macrophage colony-forming (GM-CFC) progenitor population of the hATPA/GA transduced mice were somewhat more resistant to BCNU (1.4-fold, P = 0.047) and this effect was more significant in the presence of the ATase inactivator O6-beG (3. 5-fold, P = 0.001). The polychromatic erythrocytes were also significantly protected against BCNU-induced clastogenicity both in the presence (P < 0.001) and absence of O6-beG (P < 0.05). The primitive, multipotent spleen colony-forming cells (CFU-S) in these animals also showed moderate (1.6-fold, P = 0.034) protection in the absence of O6-beG but in the presence of the inactivator they remained as sensitive to BCNU toxicity as those in the control animals (P = 0.133). This result contrasts with previous findings demonstrating significant hATPA/GA-mediated, O6-beG-resistant protection against the toxicity and clastogenicity of a number of O6-alkylating agents, including temozolomide, fotemustine and chlorozotocin. The possibility that our strategy for protective gene therapy may be highly agent and cell-type specific is unexpected and has possible implications for clinical trials of this approach using BCNU or related agents.
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subjectCancer Drug Resistanceen
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents
dc.subject.meshCarmustine
dc.subject.meshCells, Cultured
dc.subject.meshColony-Forming Units Assay
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshErythrocytes
dc.subject.meshGene Therapy
dc.subject.meshGranulocytes
dc.subject.meshGuanine
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshHumans
dc.subject.meshImmunohistochemistry
dc.subject.meshMacrophages
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMicronucleus Tests
dc.subject.meshMutagens
dc.subject.meshMutation
dc.subject.meshNucleotidyltransferases
dc.subject.meshSpleen
dc.subject.meshTransduction, Genetic
dc.titleProtection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy.en
dc.typeArticleen
dc.contributor.departmentCRC Sections of Genome Damage and Repair, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalLeukemiaen
html.description.abstractThe effect of expression of an O6-benzylguanine (O6-beG)-resistant mutant (hATPA/GA) of human O6-alkylguanine-DNA alkyltransferase (ATase) on the in vivo toxicity and clastogenicity of the anti-tumour agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to murine bone marrow has been investigated. When compared with control animals, the bipotent granulocyte-macrophage colony-forming (GM-CFC) progenitor population of the hATPA/GA transduced mice were somewhat more resistant to BCNU (1.4-fold, P = 0.047) and this effect was more significant in the presence of the ATase inactivator O6-beG (3. 5-fold, P = 0.001). The polychromatic erythrocytes were also significantly protected against BCNU-induced clastogenicity both in the presence (P < 0.001) and absence of O6-beG (P < 0.05). The primitive, multipotent spleen colony-forming cells (CFU-S) in these animals also showed moderate (1.6-fold, P = 0.034) protection in the absence of O6-beG but in the presence of the inactivator they remained as sensitive to BCNU toxicity as those in the control animals (P = 0.133). This result contrasts with previous findings demonstrating significant hATPA/GA-mediated, O6-beG-resistant protection against the toxicity and clastogenicity of a number of O6-alkylating agents, including temozolomide, fotemustine and chlorozotocin. The possibility that our strategy for protective gene therapy may be highly agent and cell-type specific is unexpected and has possible implications for clinical trials of this approach using BCNU or related agents.


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