O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow.

2.50
Hdl Handle:
http://hdl.handle.net/10541/94942
Title:
O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow.
Authors:
Chinnasamy, Nachimuthu; Rafferty, Joseph A; Hickson, Ian; Ashby, John; Tinwell, Helen; Margison, Geoffrey P; Dexter, T Michael; Fairbairn, Leslie J
Abstract:
The effects of treatment of mice with O6-benzylguanine (O6-BeG) on the levels of O6-alkylguanine-DNA alkyltransferase (ATase) in the hematopoietic compartment and on the in vivo sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with O6-BeG pretreatment were compared, dose potentiating factors of 4.17 for marrow cellularity, 4.57 for granulocyte macrophage-colony forming cells (GM-CFC) and 8.25 for colony forming unit-spleen (CFU-S) in O6-BeG pretreated versus nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although it was of lower magnitude: 1.20 for marrow cellularity, 1.63 for GM-CFC, and 1.68 for CFU-S. When the clastogenic effects of BCNU and temozolomide were examined in the mouse bone marrow micronucleus assay, a significantly (P < .05 to .001) higher frequency of micronuclei formation was observed in mice that received O6-BeG pretreatment compared with mice that received no pretreatment. These data suggest that the use of O6-BeG as a tumor-sensitizing agent before treatment of patients with O6-alkylating agents may lead to more severe hematological toxicity and possibly to an increased incidence of secondary leukemias as a result of elevated mutation frequencies in these patients.
Affiliation:
Cancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Citation:
O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow. 1997, 89 (5):1566-73 Blood
Journal:
Blood
Issue Date:
1-Mar-1997
URI:
http://hdl.handle.net/10541/94942
PubMed ID:
9057638
Type:
Article
Language:
en
ISSN:
0006-4971
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.authorHickson, Ianen
dc.contributor.authorAshby, Johnen
dc.contributor.authorTinwell, Helenen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorFairbairn, Leslie Jen
dc.date.accessioned2010-03-24T16:24:17Z-
dc.date.available2010-03-24T16:24:17Z-
dc.date.issued1997-03-01-
dc.identifier.citationO6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow. 1997, 89 (5):1566-73 Blooden
dc.identifier.issn0006-4971-
dc.identifier.pmid9057638-
dc.identifier.urihttp://hdl.handle.net/10541/94942-
dc.description.abstractThe effects of treatment of mice with O6-benzylguanine (O6-BeG) on the levels of O6-alkylguanine-DNA alkyltransferase (ATase) in the hematopoietic compartment and on the in vivo sensitivity of hematopoietic progenitor cells to the toxic and clastogenic effects of the antitumor agents 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) and temozolomide were studied. When the overall effects of BCNU alone or with O6-BeG pretreatment were compared, dose potentiating factors of 4.17 for marrow cellularity, 4.57 for granulocyte macrophage-colony forming cells (GM-CFC) and 8.25 for colony forming unit-spleen (CFU-S) in O6-BeG pretreated versus nonpretreated animals were observed. A similar trend of dose potentiation was observed for temozolomide, although it was of lower magnitude: 1.20 for marrow cellularity, 1.63 for GM-CFC, and 1.68 for CFU-S. When the clastogenic effects of BCNU and temozolomide were examined in the mouse bone marrow micronucleus assay, a significantly (P < .05 to .001) higher frequency of micronuclei formation was observed in mice that received O6-BeG pretreatment compared with mice that received no pretreatment. These data suggest that the use of O6-BeG as a tumor-sensitizing agent before treatment of patients with O6-alkylating agents may lead to more severe hematological toxicity and possibly to an increased incidence of secondary leukemias as a result of elevated mutation frequencies in these patients.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBone Marrow-
dc.subject.meshBone Marrow Cells-
dc.subject.meshCarmustine-
dc.subject.meshCell Division-
dc.subject.meshDacarbazine-
dc.subject.meshDrug Synergism-
dc.subject.meshFemale-
dc.subject.meshGuanine-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshMale-
dc.subject.meshMice-
dc.titleO6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalBlooden

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