A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase.

Published

Journal Article

Administration of chemotherapy is often limited by myelosuppression. Expression of drug-resistance genes in hematopoietic cells has been proposed as a means to decrease the toxicity of cytotoxic agents. In this pilot study, we utilized a retroviral vector expressing methylguanine DNA methyltransferase (MGMT) to transduce hematopoietic progenitors, which were subsequently used in the setting of alkylator therapy (procarbazine, CCNU, vincristine (PCV)) for poor prognosis brain tumors. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells were collected by apheresis and enriched for CD34+ expression. Nine subjects were infused with CD34+-enriched cells treated in a transduction procedure involving a 4-day exposure to cytokines with vector exposure on days 3 and 4. No major adverse event was related to the gene therapy procedure. Importantly, the engraftment kinetics of the treated product was similar to unmanipulated peripheral blood stem cells, suggesting that the ex vivo manipulation did not significantly reduce engrafting progenitor cell function. Gene-transduced cells were detected in all subjects. Although the level and duration was limited, patients receiving cells transduced using fibronectin 'preloaded' with virus supernatant appeared to show improved in vivo marking frequency. These findings demonstrate the feasibility and safety of utilizing MGMT-transduced CD34+ peripheral blood progenitor cells in the setting of chemotherapy.

Full Text

Duke Authors

Cited Authors

  • Cornetta, K; Croop, J; Dropcho, E; Abonour, R; Kieran, MW; Kreissman, S; Reeves, L; Erickson, LC; Williams, DA

Published Date

  • September 2006

Published In

Volume / Issue

  • 13 / 9

Start / End Page

  • 886 - 895

PubMed ID

  • 16645619

Pubmed Central ID

  • 16645619

Electronic International Standard Serial Number (EISSN)

  • 1476-5500

International Standard Serial Number (ISSN)

  • 0929-1903

Digital Object Identifier (DOI)

  • 10.1038/sj.cgt.7700963

Language

  • eng