Study of cancer gene therapy using IL-12-secreting endothelial progenitor cells in a rat solid tumor model.
To test the hypothesis that genetically modified bone marrow-derived endothelial progenitor cells (EPCs) can be effective carriers of therapeutic agents to tumor sites, we utilized our conditionally immortalized endothelial progenitor cell line, TR-BME-2. In the syngenic rat, systemically injected TR-BME-2 cells were immediately distributed to the organs (lung, bone marrow, peripheral blood, liver, spleen). Trapped cells were cleared within 4 days, but selective accumulation in the Walker256 tumor was maintained for over 4 days. The tumor growth was enhanced by administration of TR-BME-2 cells. It is suggested that accumulated TR-BME-2 differentiated to tumor vasculature, increased the tumor blood supply, and thereby increased the tumor volume. We conducted IL-12 gene transfection of TR-BME-2 cells with a virus vector in vitro, and used the resultant IL-12-secreting TR-BME-2 to deliver IL-12, which strongly activates cytotoxic lymphocytes and natural killer cells, to the tumor site in vivo. However, the tumor-progressive character of TR-BME-2 offset the anti-tumor effect of IL-12. Nevertheless, our results suggest that gene-transfected EPCs could be useful as a tumor-specific drug delivery system, especially if the tumor vasculature-promoting effect of EPCs can be blocked.
Muta
Mariko
M
Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo 113-8677, Japan.
Matsumoto
Gaku
G
Hiruma
Kiyoshi
K
Nakashima
Emi
E
Toi
Masakazu
M
D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D009930:Organic Chemicals / Q000494:pharmacology; D051381:Rats; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection
D005456:Fluorescent Dyes; D009930:Organic Chemicals; C070080:PKH 26; D018664:Interleukin-12