Hematoprotection and enrichment of transduced cells in vivo after gene transfer of MGMTP140k into hematopoietic stem cells

Michael Jansen, Ursula R. Sorg, Susanne Ragg, Michael Flasshove, Siegfried Seeber, David A. Williams, Thomas Moritz

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The overexpression of mutant forms of O6 -methylguanine-DNA-methyltransferase (MGMT), resistant to the MGMT inhibitor O6-benzylguanine (BG), protects hematopoietic cells from the toxicity of combined BG plus O6-alkylating agent chemotherapy. To evaluate the feasibility of this approach for clinically relevant O6-alkylating agents, combined therapy with BG and two chloroethylnitrosourea-type drugs, ACNU or BCNU, or the triazene derivative temozolomide (TMZ) was investigated in a murine bone marrow transplant model allowing transgenic expression of the highly BG-resistant MGMTP14OK mutant. Whereas 20/20 control animals transplanted with nontransduced cells died of progressive myelosuppression during therapy, nearly all animals transplanted with MGMTP14OK-transduced cells survived treatment with BG/ACNU (12/15), BG/TMZ (10/10), or BG/BCNU (5/5). In surviving animals, hematological parameters improved during chemotherapy and pretreatment levels were reestablished during or shortly after therapy. All animals showed enrichment of transgenic granulocytes (range: 15- to 101-fold) and lymphocytes (range: 16- to 55-fold) in peripheral blood, bone marrow, and spleen. No significant differences were observed between individual treatment groups. Serial transplants demonstrated protection in secondary recipients and confirmed the transduction of transplantable stem cells. Thus, these data demonstrate efficient protection from hematotoxicity and substantial enrichment of transgenic cells following MGMTP14OK gene transfer and treatment with different O6-alkylating drugs.

Original languageEnglish (US)
Pages (from-to)737-746
Number of pages10
JournalCancer gene therapy
Volume9
Issue number9
DOIs
StatePublished - Jan 1 2002

Keywords

  • Chloroethylnitrosoureas
  • DNA repair
  • Gene therapy
  • O-methylguanine-DNA-methyltransferase
  • Retroviral vectors
  • Temozolomide

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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