O6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide.

2.50
Hdl Handle:
http://hdl.handle.net/10541/97949
Title:
O6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide.
Authors:
Fairbairn, Leslie J; Watson, Amanda J; Rafferty, Joseph A; Elder, Rhoderick H; Margison, Geoffrey P
Abstract:
The sensitivity of human primary bone marrow granulocyte/macrophage precursor cells to the cytotoxic effects of the methylating antitumor agent temozolomide (8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-[3H]-1) was investigated using an in vitro colony-forming assay. In the eight samples examined, there was a range of sensitivities with D37 values from 18.2 to > 55 microM. When cells were simultaneously exposed to the O6-alkylguanine-DNA alkyltransferase (ATase) inactivating agent, O6-benzylguanine (O6BeG; 10 microM), the cytotoxicity of temozolomide was substantially increased with D37 values between 5 and 38.5 microM. O6BeG also increased temozolomide sensitivity in the human colon carcinoma cell line, WiDr, and this was shown to correlate with the O6BeG-mediated depletion of ATase activity. Where the extent of sensitization produced by O6BeG could be calculated, there was a correlation between this and the D37 value in the absence of O6BeG (R = 0.996); thus, sensitization was more extensive in the cells that were inherently more resistant to temozolomide. These data have implications for possible increased hematological toxicity in clinical protocols designed to exploit O6BeG or other agents to deplete ATase activity in tumors cells prior to treatment of patients with temozolomide or related agents.
Affiliation:
Cancer Research Campaign Department, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Citation:
O6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide. 1995, 23 (2):112-6 Exp. Hematol.
Journal:
Experimental Hematology
Issue Date:
Feb-1995
URI:
http://hdl.handle.net/10541/97949
PubMed ID:
7828668
Type:
Article
Language:
en
ISSN:
0301-472X
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorFairbairn, Leslie Jen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorRafferty, Joseph Aen
dc.contributor.authorElder, Rhoderick Hen
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2010-05-05T12:43:54Z-
dc.date.available2010-05-05T12:43:54Z-
dc.date.issued1995-02-
dc.identifier.citationO6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide. 1995, 23 (2):112-6 Exp. Hematol.en
dc.identifier.issn0301-472X-
dc.identifier.pmid7828668-
dc.identifier.urihttp://hdl.handle.net/10541/97949-
dc.description.abstractThe sensitivity of human primary bone marrow granulocyte/macrophage precursor cells to the cytotoxic effects of the methylating antitumor agent temozolomide (8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-[3H]-1) was investigated using an in vitro colony-forming assay. In the eight samples examined, there was a range of sensitivities with D37 values from 18.2 to > 55 microM. When cells were simultaneously exposed to the O6-alkylguanine-DNA alkyltransferase (ATase) inactivating agent, O6-benzylguanine (O6BeG; 10 microM), the cytotoxicity of temozolomide was substantially increased with D37 values between 5 and 38.5 microM. O6BeG also increased temozolomide sensitivity in the human colon carcinoma cell line, WiDr, and this was shown to correlate with the O6BeG-mediated depletion of ATase activity. Where the extent of sensitization produced by O6BeG could be calculated, there was a correlation between this and the D37 value in the absence of O6BeG (R = 0.996); thus, sensitization was more extensive in the cells that were inherently more resistant to temozolomide. These data have implications for possible increased hematological toxicity in clinical protocols designed to exploit O6BeG or other agents to deplete ATase activity in tumors cells prior to treatment of patients with temozolomide or related agents.en
dc.language.isoenen
dc.subject.meshAlkylating Agents-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBone Marrow-
dc.subject.meshBone Marrow Cells-
dc.subject.meshCells, Cultured-
dc.subject.meshColony-Forming Units Assay-
dc.subject.meshDacarbazine-
dc.subject.meshGranulocytes-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshMacrophages-
dc.subject.meshMethyltransferases-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.titleO6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Department, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalExperimental Hematologyen

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