Hematopoietic expression of O6-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O6-benzylguanine and 1,3-bis-(2-chloroethyl)-1- nitrosourea

Emiko L. Kreklau, Karen Pollok, Barbara J. Bailey, Naili Liu, Jennifer R. Hartwell, David A. Williams, Leonard C. Erickson

Research output: Contribution to journalArticle

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Abstract

The major mechanism of tumor cell resistance to 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU) is the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). This repair system can be temporarily inhibited by the free base O6-benzylguanine (BG), which depletes cellular MGMT activity and sensitizes tumor cells and xenografts to BCNU. In clinical studies, the combination of BG and BCNU enhanced the myeloid toxicity of BCNU, thereby reducing the maximum tolerated dose. We have shown previously that retroviral expression of the P140K mutant of MGMT (MGMT-P140K) in murine and human hematopoietic cells produces significant resistance of bone marrow cells to low-dose, combination BG and BCNU treatment in vivo. In the current study, we investigated the ability of bone marrow transplantation with MGMT-P140K-transduced hematopoietic cells to protect against an intensive antitumor treatment regimen of combination BG and BCNU in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The donor marrow cells underwent in vivo BG and BCNU selection before transplantation, allowing infusion of a highly selected population of transduced cells. Tolerance to the intensive BG and BCNU treatment was markedly improved in secondary MGMT-P140K-transplanted mice (n = 19) compared to untransplanted mice (n = 15), as indicated by blood counts and survival rate. The dose-intensified BG and BCNU therapy produced significant growth delays of glioma xenografts in MGMT-P140K-transplanted mice, extending the tumor doubling time by >40 days. These results demonstrate that MGMT-P140K-transduced bone marrow protects against BG and BCNU combination therapy in vivo and allows dose-intensified treatment of tumor xenografts.

Original languageEnglish
Pages (from-to)1321-1329
Number of pages9
JournalMolecular Cancer Therapeutics
Volume2
Issue number12
StatePublished - Dec 2003

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Carmustine
Methyltransferases
Heterografts
Glioma
DNA
Therapeutics
Neoplasms
O-(6)-methylguanine
O(6)-benzylguanine
Bone Marrow
SCID Mice
Maximum Tolerated Dose
Bone Marrow Transplantation
DNA Repair
Bone Marrow Cells
Transplantation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Hematopoietic expression of O6-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O6-benzylguanine and 1,3-bis-(2-chloroethyl)-1- nitrosourea. / Kreklau, Emiko L.; Pollok, Karen; Bailey, Barbara J.; Liu, Naili; Hartwell, Jennifer R.; Williams, David A.; Erickson, Leonard C.

In: Molecular Cancer Therapeutics, Vol. 2, No. 12, 12.2003, p. 1321-1329.

Research output: Contribution to journalArticle

Kreklau, Emiko L. ; Pollok, Karen ; Bailey, Barbara J. ; Liu, Naili ; Hartwell, Jennifer R. ; Williams, David A. ; Erickson, Leonard C. / Hematopoietic expression of O6-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O6-benzylguanine and 1,3-bis-(2-chloroethyl)-1- nitrosourea. In: Molecular Cancer Therapeutics. 2003 ; Vol. 2, No. 12. pp. 1321-1329.
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abstract = "The major mechanism of tumor cell resistance to 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU) is the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). This repair system can be temporarily inhibited by the free base O6-benzylguanine (BG), which depletes cellular MGMT activity and sensitizes tumor cells and xenografts to BCNU. In clinical studies, the combination of BG and BCNU enhanced the myeloid toxicity of BCNU, thereby reducing the maximum tolerated dose. We have shown previously that retroviral expression of the P140K mutant of MGMT (MGMT-P140K) in murine and human hematopoietic cells produces significant resistance of bone marrow cells to low-dose, combination BG and BCNU treatment in vivo. In the current study, we investigated the ability of bone marrow transplantation with MGMT-P140K-transduced hematopoietic cells to protect against an intensive antitumor treatment regimen of combination BG and BCNU in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The donor marrow cells underwent in vivo BG and BCNU selection before transplantation, allowing infusion of a highly selected population of transduced cells. Tolerance to the intensive BG and BCNU treatment was markedly improved in secondary MGMT-P140K-transplanted mice (n = 19) compared to untransplanted mice (n = 15), as indicated by blood counts and survival rate. The dose-intensified BG and BCNU therapy produced significant growth delays of glioma xenografts in MGMT-P140K-transplanted mice, extending the tumor doubling time by >40 days. These results demonstrate that MGMT-P140K-transduced bone marrow protects against BG and BCNU combination therapy in vivo and allows dose-intensified treatment of tumor xenografts.",
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AU - Erickson, Leonard C.

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