|
|
 Previous Article | Table of Contents | Next Article 
O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of
temozolomide and BCNU in mouse bone marrow
N Chinnasamy, JA Rafferty, I Hickson, J Ashby, H Tinwell, GP Margison, TM Dexter and LJ Fairbairn
Cancer Research Campaign Department of Carcinogenesis, Paterson Institute
for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
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.
Volume 89,
Issue 5,
pp. 1566-1573,
03/01/1997
Copyright © 1997 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
N. J. Curtin, L.-Z. Wang, A. Yiakouvaki, S. Kyle, C. A. Arris, S. Canan-Koch, S. E. Webber, B. W. Durkacz, H. A. Calvert, Z. Hostomsky, et al.
Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells
Clin. Cancer Res.,
February 1, 2004;
10(3):
881 - 889.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Kokkinakis, R. M. Hoffman, E. P. Frenkel, J. B. Wick, Q. Han, M. Xu, Y. Tan, and S. C. Schold
Synergy between Methionine Stress and Chemotherapy in the Treatment of Brain Tumor Xenografts in Athymic Mice
Cancer Res.,
May 1, 2001;
61(10):
4017 - 4023.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
E. L. Kreklau, N. Liu, Z. Li, K. Cornetta, and L. C. Erickson
Comparison of Single- Versus Double-Bolus Treatments of O6-Benzylguanine for Depletion of O6-Methylguanine DNA Methyltransferase (MGMT) Activity in Vivo: Development of a Novel Fluorometric Oligonucleotide Assay for Measurement of Mgmt Activity
J. Pharmacol. Exp. Ther.,
April 12, 2001;
297(2):
524 - 530.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. M. Kokkinakis, D. B. Bocangel, S. C. Schold, R. C. Moschel, and A. E. Pegg
Thresholds of O6-Alkylguanine-DNA Alkyltransferase which Confer Significant Resistance of Human Glial Tumor Xenografts to Treatment with 1,3-Bis(2-chloroethyl)-1-nitrosourea or Temozolomide
Clin. Cancer Res.,
February 1, 2001;
7(2):
421 - 428.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Cai, M. H. Wu, M. Xu-Welliver, A. E. Pegg, S. M. Ludeman, and M. E. Dolan
Effect of O6-Benzylguanine on Alkylating Agent-induced Toxicity and Mutagenicity in Chinese Hamster Ovary Cells Expressing Wild-Type and Mutant O6-Alkylguanine-DNA Alkyltransferases
Cancer Res.,
October 1, 2000;
60(19):
5464 - 5469.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. S. Friedman, T. Kerby, and H. Calvert
Temozolomide and Treatment of Malignant Glioma
Clin. Cancer Res.,
July 1, 2000;
6(7):
2585 - 2597.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
N. J. Toft, O. J. Sansom, R. A. Brookes, M. J. Arends, M. Wood, G. P. Margison, D. J. Winton, and A. R. Clarke
In vivo administration of O6-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine
Carcinogenesis,
April 1, 2000;
21(4):
593 - 598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Clemons, A. Watson, A. Howell, J. Chang, C. Heyworth, B. Lord, N. Testa, T. M. Dexter, and G. Margison
Macrophage Inflammatory Protein 1{{alpha}} Attenuates the Toxic Effects of Temozolomide in Human Bone Marrow Granulocyte- Macrophage Colony-forming Cells
Clin. Cancer Res.,
March 1, 2000;
6(3):
966 - 970.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C. D. Britten, E. K. Rowinsky, S. D. Baker, S. S. Agarwala, J. R. Eckardt, R. Barrington, S. G. Diab, L. A. Hammond, T. Johnson, M. Villalona-Calero, et al.
A Phase I and Pharmacokinetic Study of Temozolomide and Cisplatin in Patients with Advanced Solid Malignancies
Clin. Cancer Res.,
July 1, 1999;
5(7):
1629 - 1637.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Reese, B. M. Davis, L. Liu, and S. L. Gerson
Simultaneous Protection of G156A Methylguanine DNA Methyltransferase Gene-transduced Hematopoietic Progenitors and Sensitization of Tumor Cells Using O6-Benzylguanine and Temozolomide
Clin. Cancer Res.,
January 1, 1999;
5(1):
163 - 169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Elder, J. G. Jansen, R. J. Weeks, M. A. Willington, B. Deans, A. J. Watson, K. J. Mynett, J. A. Bailey, D. P. Cooper, J. A. Rafferty, et al.
Alkylpurine-DNA-N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate
Mol. Cell. Biol.,
October 1, 1998;
18(10):
5828 - 5837.
[Abstract]
[Full Text]
|
|
|
| |
