Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy.

2.50
Hdl Handle:
http://hdl.handle.net/10541/90155
Title:
Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy.
Authors:
Chinnasamy, Nachimuthu; Rafferty, Joseph A; Lashford, Linda S; Chinnasamy, Dhanalakshmi; Margison, Geoffrey P; Thatcher, Nick; Dexter, T Michael; Fairbairn, Leslie J
Abstract:
The 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.
Affiliation:
CRC Sections of Genome Damage and Repair, Paterson Institute for Cancer Research, Manchester, UK.
Citation:
Protection 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 Leukemia
Journal:
Leukemia
Issue Date:
Nov-1999
URI:
http://hdl.handle.net/10541/90155
PubMed ID:
10557052
Type:
Article
Language:
en
ISSN:
0887-6924
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorChinnasamy, Nachimuthuen
dc.contributor.authorRafferty, Joseph Aen
dc.contributor.authorLashford, Linda Sen
dc.contributor.authorChinnasamy, Dhanalakshmien
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorThatcher, Nicken
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorFairbairn, Leslie Jen
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.en
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

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