|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3078-3084
Limiting numbers of G156A
O6-methylguanine-DNA methyltransferase-transduced marrow
progenitors repopulate nonmyeloablated mice after drug selection
Brian M. Davis,
Omer N. Koç, and
Stanton L. Gerson
From the Division of Hematology/Oncology, Case Western Reserve
University, the Molecular Virology Training Program, and the Ireland
Cancer Center, University Hospitals of Cleveland, Cleveland, OH.
The limited efficacy of hematopoietic gene therapy can be improved
by in vivo selection for transduced long-term repopulating cells
(LTRC). We selected for G156A MGMT ( MGMT) transduced LTRC present in
5 × 104 to 100 × 104 marrow cells
infused into nonmyeloablated mice by the administration of
O6-benzylguanine (BG) and BCNU every 3 to 4 weeks. To
facilitate engraftment, mice were given a nonablative dose of BG and
BCNU before infusion. Without selection, MGMT was not detected in any hematopoietic colony-forming units (CFU) 24 to 30 weeks after infusion. After BG and BCNU, MGMT+ CFU were frequently
detected, and their proportions increased with each treatment cycle.
After 2 to 3 cycles of BG and BCNU, many mice were stably reconstituted
with 75% to 100% MGMT+ CFU for at least 6 months,
representing up to 940-fold enrichment. Thus, BG and BCNU stem cell
toxicity allows MGMT-transduced LTRC to repopulate the bone marrow.
This degree of selection pressure in nonmyeloablated mice is far
greater than that observed in previous drug-resistance gene transfer
studies. These data support our approved clinical trial to select for
drug-resistant, transduced hematopoietic cells, potentially decreasing
cumulative drug-induced myelosuppression in patients with cancer. These
data also suggest that MGMT may be a potent, dominant, selectable
marker for use in dual gene therapy.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. Zhao, T. I. Pestina, M. Nasimuzzaman, P. Mehta, P. W. Hargrove, and D. A. Persons
Amelioration of murine {beta}-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both {gamma}-globin and the MGMT drug-resistance gene
Blood,
June 4, 2009;
113(23):
5747 - 5756.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. C. Beard, R. Sud, K. A. Keyser, C. Ironside, T. Neff, S. Gerull, G. D. Trobridge, and H.-P. Kiem
Long-term polyclonal and multilineage engraftment of methylguanine methyltransferase P140K gene-modified dog hematopoietic cells in primary and secondary recipients
Blood,
May 21, 2009;
113(21):
5094 - 5103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. J. Lee, P. Kahatapitiya, B. Kramer, J. E. Joya, J. Hook, R. Liu, G. Schevzov, I. E. Alexander, G. McCowage, D. Montarras, et al.
Methylguanine DNA Methyltransferase-Mediated Drug Resistance-Based Selective Enrichment and Engraftment of Transplanted Stem Cells in Skeletal Muscle
Stem Cells,
May 1, 2009;
27(5):
1098 - 1108.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. C. Porter and J. DeGregori
Interfering RNA-mediated purine analog resistance for in vitro and in vivo cell selection
Blood,
December 1, 2008;
112(12):
4466 - 4474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Lee, J. E. Dennis, and S. L. Gerson
Imaging Stem Cell Implant for Cellular-Based Therapies
Experimental Biology and Medicine,
August 1, 2008;
233(8):
930 - 940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Reese, J. C. Roth, and S. L. Gerson
Bone Marrow-Derived Cells Exhibiting Lung Epithelial Cell Characteristics Are Enriched In Vivo Using Methylguanine DNA Methyltransferase-Mediated Drug Resistance
Stem Cells,
March 1, 2008;
26(3):
675 - 681.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. R. Ball, I. H. Pilz, M. Schmidt, S. Fessler, D. A. Williams, C. von Kalle, and H. Glimm
Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression
Blood,
September 15, 2007;
110(6):
1779 - 1787.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Neff, B. C. Beard, and H.-P. Kiem
Survival of the fittest: in vivo selection and stem cell gene therapy
Blood,
March 1, 2006;
107(5):
1751 - 1760.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Liu and S. L. Gerson
Targeted Modulation of MGMT: Clinical Implications
Clin. Cancer Res.,
January 15, 2006;
12(2):
328 - 331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Fontes, B. M. Davis, L. P. Encell, K. Lingas, D. T. Covas, M. A. Zago, L. A. Loeb, A. E. Pegg, and S. L. Gerson
Differential competitive resistance to methylating versus chloroethylating agents among five O6-alkylguanine DNA alkyltransferases in human hematopoietic cells
Mol. Cancer Ther.,
January 1, 2006;
5(1):
121 - 128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Gerson
Selection without harm: drug resistance gene therapy hits the big time
Blood,
February 1, 2005;
105(3):
914 - 914.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. E. Richard, M. Weinreich, K.-H. Chang, J. Ieremia, M. M. Stevenson, and C. A. Blau
Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency
Blood,
June 15, 2004;
103(12):
4432 - 4439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Persons, J. A. Allay, A. Bonifacino, T. Lu, B. Agricola, M. E. Metzger, R. E. Donahue, C. E. Dunbar, and B. P. Sorrentino
Transient in vivo selection of transduced peripheral blood cells using antifolate drug selection in rhesus macaques that received transplants with hematopoietic stem cells expressing dihydrofolate reductase vectors
Blood,
February 1, 2004;
103(3):
796 - 803.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Persons, E. R. Allay, N. Sawai, P. W. Hargrove, T. P. Brent, H. Hanawa, A. W. Nienhuis, and B. P. Sorrentino
Successful treatment of murine {beta}-thalassemia using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells
Blood,
July 15, 2003;
102(2):
506 - 513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Neff, P. A. Horn, V. E. Valli, A. M. Gown, S. Wardwell, B. L. Wood, C. von Kalle, M. Schmidt, L. J. Peterson, J. C. Morris, et al.
Pharmacologically regulated in vivo selection in a large animal
Blood,
August 28, 2002;
100(6):
2026 - 2031.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D. Bacolod, S. P. Johnson, F. Ali-Osman, P. Modrich, N. S. Bullock, O. M. Colvin, D. D. Bigner, and H. S. Friedman
Mechanisms of Resistance to 1,3-Bis(2-chloroethyl)-1-nitrosourea in Human Medulloblastoma and Rhabdomyosarcoma
Mol. Cancer Ther.,
July 1, 2002;
1(9):
727 - 736.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Gerson
Clinical Relevance of MGMT in the Treatment of Cancer
J. Clin. Oncol.,
May 1, 2002;
20(9):
2388 - 2399.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Warlick, M. D. Diers, J. E. Wagner, and R. S. McIvor
In Vivo Selection of Antifolate-Resistant Transgenic Hematopoietic Stem Cells in a Murine Bone Marrow Transplant Model
J. Pharmacol. Exp. Ther.,
January 1, 2002;
300(1):
50 - 56.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kobune, Y. Xu, C. Baum, M. R. Kelley, and D. A. Williams
Retrovirus-mediated Expression of the Base Excision Repair Proteins, Formamidopyrimidine DNA Glycosylase or Human Oxoguanine DNA Glycosylase, Protects Hematopoietic Cells from N,N',N''-Triethylenethiophosphoramide (thioTEPA)-induced Toxicity in Vitro and in Vivo
Cancer Res.,
July 1, 2001;
61(13):
5116 - 5125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Persons, E. R. Allay, D. E. Sabatino, P. Kelly, D. M. Bodine, and A. W. Nienhuis
Functional requirements for phenotypic correction of murine {beta}-thalassemia: implications for human gene therapy
Blood,
May 15, 2001;
97(10):
3275 - 3282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. M. Davis, L. P. Encell, S. P. Zielske, F. C. Christians, L. Liu, S. E. Friebert, L. A. Loeb, and S. L. Gerson
Applied molecular evolution of O6-benzylguanine-resistant DNA alkyltransferases in human hematopoietic cells
PNAS,
April 5, 2001;
(2001)
91601198.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Hanazono, K. Terao, and K. Ozawa
Gene Transfer into Nonhuman Primate Hematopoietic Stem Cells: Implications for Gene Therapy
Stem Cells,
January 1, 2001;
19(1):
12 - 23.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. M. Davis, L. P. Encell, S. P. Zielske, F. C. Christians, L. Liu, S. E. Friebert, L. A. Loeb, and S. L. Gerson
Applied molecular evolution of O6-benzylguanine-resistant DNA alkyltransferases in human hematopoietic cells
PNAS,
April 24, 2001;
98(9):
4950 - 4954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
