Selective elimination (purging) of contaminating malignant cells from hematopoietic stem cell autografts using recombinant adenovirus.
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.
Wroblewski
J M
JM
Department of Medicine, University of Kentucky, Lexington, USA.
Lay
L T
LT
Van Zant
G
G
Phillips
G
G
Seth
P
P
Curiel
D
D
Meeker
T C
TC
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
D000998:Antiviral Agents; D016159:Tumor Suppressor Protein p53; D013937:Thymidine Kinase; D015774:Ganciclovir