title: Selective elimination (purging) of contaminating malignant cells from hematopoietic stem cell autografts using recombinant adenovirus.
abstract: In this work we have explored the use of adenoviral vectors for the purging of cancer cells from hematopoietic stem cell (HSC) autografts. We showed that a recombinant adenovirus expressing the herpes simplex-1 thymidine kinase gene (AD-tk) plus ganciclovir (GCV) killed HELA cells more effectively than did GCV alone. HELA cells were then mixed with human HSCs and exposed to AD-tk/GCV. AD-tk/GCV reduced the number of HELA colonies to 4% of control values, with no detectable reduction in the hematopoietic progenitor, colony forming unit-granulocyte/monocyte (CFU-GM). Similar studies of the JB6 non-Hodgkins lymphoma cell line showed a reduction to 5% of controls; studies of MCF-7, a breast carcinoma cell line, showed a reduction to 30% of controls, with no CFU-GM toxicity. Thus, AD-tk mediated selective killing of contaminating tumor cells. We also evaluated a recombinant adenovirus encoding the tumor suppressor gene p53 (AD-p53). AD-p53 was able to selectively kill all three cell lines (reducing tumor colonies approximately 100-fold) without any toxicity to CFU-GM. Although both AD-tk/GCV and AD-p53 were effective in these experiments, AD-p53 seemed to be more potent. Adenoviral vectors show promise for selectively targeting cancer cells that contaminate HSC autografts.
authors.affiliation: Department of Medicine, University of Kentucky, Lexington, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Wroblewski
authors.forename: L T
authors.initials: LT
authors.lastname: Lay
authors.forename: G
authors.initials: G
authors.lastname: Van Zant
authors.forename: G
authors.initials: G
authors.lastname: Phillips
authors.forename: P
authors.initials: P
authors.lastname: Seth
authors.forename: D
authors.initials: D
authors.lastname: Curiel
authors.forename: T C
authors.initials: TC
authors.lastname: Meeker
mesh_terms: D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics*; D000998:Antiviral Agents / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D011995:Recombination, Genetic; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D016159:Tumor Suppressor Protein p53; D013937:Thymidine Kinase; D015774:Ganciclovir