Ex vivo breast cancer cell purging by adenovirus-mediated cytosine deaminase gene transfer and short-term incubation with 5-fluorocytosine completely prevents tumor growth after transplantation.
Peripheral blood progenitor harvests of breast cancer patients are contaminated with tumor cells, suggesting a potential role for these cells in the relapse after high-dose chemotherapy. Whereas physical purging methods do not eliminate contaminating tumor cells completely, pharmacological purging, although highly efficient, is hampered by a strong nonspecific toxicity toward hematopoietic progenitor cells. Taking advantage of the high efficiency of adenovirus-mediated gene transfer to epithelial cells, we selectively loaded breast cancer cells in vitro with a cytotoxic drug by gene transfer of the prodrug-converting enzyme cytosine deaminase (AdCMV.CD) and 5-fluorocytosine (5-FC). Despite the low dose of vector administered, limited exposure to 5-FC, and transplantation only of viable tumor cells into SCID mice, all animals that received cells treated in vitro with AdCMV.CD plus 5-FC were completely free of tumor development. These data show that the selective loading of tumor cells with AdCMV.CD/5-FC might be useful for purging of autografts.
Wolff
G
G
Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Klinik, University Medical Center, Charité, Humboldt University of Berlin, Germany.
Körner
I J
IJ
Schumacher
A
A
Arnold
W
W
Dörken
B
B
Mapara
M Y
MY
D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001943:Breast Neoplasms / Q000473:pathology*; D043525:Cytosine Deaminase; D005260:Female; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil