Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells.
dc.contributor.author | Chinnasamy, Nachimuthu | |
dc.contributor.author | Fairbairn, Leslie J | |
dc.contributor.author | Laher, J | |
dc.contributor.author | Willington, Mark | |
dc.contributor.author | Rafferty, Joseph A | |
dc.date.accessioned | 2010-02-23T09:33:43Z | |
dc.date.available | 2010-02-23T09:33:43Z | |
dc.date.issued | 1998-08-07 | |
dc.identifier.citation | Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells. 1998, 416 (1-2):1-10 Mutat. Res. | en |
dc.identifier.issn | 0027-5107 | |
dc.identifier.pmid | 9725988 | |
dc.identifier.uri | http://hdl.handle.net/10541/92695 | |
dc.description.abstract | The murine bone marrow micronucleus assay has been used to examine (1) the potentiation of fotemustine and streptozotocin induced-clastogenicity by the O6-alkylguanine-DNA alkyltransferase (ATase) inactivator O6-benzylguanine (O6-beG) and (2) the level of protection afforded against this potentiation by retrovirus-mediated expression of an O6-beG-resistant mutant of human ATase (haTPA/GA) in mouse bone marrow. Both fotemustine and streptozotocin induced significantly higher levels of micronucleated polychromatic erythrocytes (p < 0.001 for the highest doses studied) compared to those seen in vehicle-treated animals. The number of micronuclei produced by either agent was dramatically elevated by pretreatment with O6-beG (p < 0.001). Furthermore, in myeloablated mice reconstituted with bone marrow expressing the O6-beG-resistant hATPA/GA as a result of retroviral gene transfer, the frequency of micronucleus formation following exposure of mice to otherwise clastogenic doses of fotemustine or streptozotocin, in the presence of O6-beG, wash highly significantly reduced (p < 0.001 for both agents) relative to that in mock transduced controls. These data clearly implicate O6-chloroethyl- and O6-methylguanine as clastogenic lesions in vivo and establish ATase as a major protective mechanism operating to reduce the frequency of such damage. The potentiation of drug induced clastogenicity by O6-beG suggests that the clinical use of this inactivator in combination with O6-alkylating agents, could substantially increase the risk of therapy related malignancy. Nevertheless the use of hATPA/GA as a protective mechanism via gene therapy may overcome this risk. | |
dc.language.iso | en | en |
dc.subject.mesh | Alkyl and Aryl Transferases | |
dc.subject.mesh | Alkylating Agents | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Bone Marrow Cells | |
dc.subject.mesh | Bone Marrow Transplantation | |
dc.subject.mesh | DNA Repair | |
dc.subject.mesh | Drug Synergism | |
dc.subject.mesh | Enzyme Inhibitors | |
dc.subject.mesh | Female | |
dc.subject.mesh | Gene Expression | |
dc.subject.mesh | Guanine | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Micronucleus Tests | |
dc.subject.mesh | Mutagens | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Nitrosourea Compounds | |
dc.subject.mesh | Organophosphorus Compounds | |
dc.subject.mesh | Streptozocin | |
dc.title | Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells. | en |
dc.type | Article | en |
dc.contributor.department | CRC Section of Haemopoietic Cell, Paterson Institute for Cancer Research, Christine Hospital NHS Trust, Mancester M20 4BX, UK. | en |
dc.identifier.journal | Mutation Research | en |
html.description.abstract | The murine bone marrow micronucleus assay has been used to examine (1) the potentiation of fotemustine and streptozotocin induced-clastogenicity by the O6-alkylguanine-DNA alkyltransferase (ATase) inactivator O6-benzylguanine (O6-beG) and (2) the level of protection afforded against this potentiation by retrovirus-mediated expression of an O6-beG-resistant mutant of human ATase (haTPA/GA) in mouse bone marrow. Both fotemustine and streptozotocin induced significantly higher levels of micronucleated polychromatic erythrocytes (p < 0.001 for the highest doses studied) compared to those seen in vehicle-treated animals. The number of micronuclei produced by either agent was dramatically elevated by pretreatment with O6-beG (p < 0.001). Furthermore, in myeloablated mice reconstituted with bone marrow expressing the O6-beG-resistant hATPA/GA as a result of retroviral gene transfer, the frequency of micronucleus formation following exposure of mice to otherwise clastogenic doses of fotemustine or streptozotocin, in the presence of O6-beG, wash highly significantly reduced (p < 0.001 for both agents) relative to that in mock transduced controls. These data clearly implicate O6-chloroethyl- and O6-methylguanine as clastogenic lesions in vivo and establish ATase as a major protective mechanism operating to reduce the frequency of such damage. The potentiation of drug induced clastogenicity by O6-beG suggests that the clinical use of this inactivator in combination with O6-alkylating agents, could substantially increase the risk of therapy related malignancy. Nevertheless the use of hATPA/GA as a protective mechanism via gene therapy may overcome this risk. |