Breast cancer gene therapy: transgenic immunotherapy.
A number of studies have demonstrated that potent anti-tumor immunity can be induced using cytokine gene transfer, a strategy termed transgenic immunotherapy. Our aim is to express cytokine genes in the vicinity of tumor cells, either by transducing tumor cells themselves, or by delivering cytokine-expressing endothelial cells to tumor sites. We compared the ability of cytokine-expressing tumor cells or endothelial cells to inhibit the tumorigenesis of MDA-MB-435 breast cancer cells in athymic nude mice. Retroviral vectors containing either human interleukin 2 (hIL-2) or interleukin 1 (hIL-1 alpha) were used to transduce MDA-MB-435 cells or human umbilical vein endothelial cells (HUVEC). Using a modified MTT bioassay and an ELISA specific for hIL-2, 43 of 70 MDA-MB-435 clones transduced with IL-2 were found to secrete between 100-800 units of IL-2/10(6) cells/24 hr. hIL-2 and hIL-1 alpha-transduced HUVEC secreted 40 ng/IL-2/10(6)/24 hr and 1.8 ng/10(6)/24 hr, respectively. To facilitate in vivo tracking of tumor cells, both nontransduced and IL-2-expressing MDA-MB-435 cells were genetically-marked with the E. coli lacZ gene and selected using flow cytometry. To study in vivo tumorigenicity, cells were injected into the mammary fat pad of athymic nude mice: (1) lacZ/MDA-MB-435 cells injected alone formed tumors in all animals; (2) IL-2-expressing lacZ/MDA-MB-435 cells did not form any tumors; (3) co-inoculation of MDA-MB-435/IL-2, or HUVEC/IL-2, or HUVEC/IL-1 alpha with lacZ/MDA-MB-435 cells prevented or delayed tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Medicine (Division of Hematology), Georgetown University Medical Center, Washington, DC 20007.
Ojeifo
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MacPherson
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Zwiebel
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D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D015316:Genetic Therapy; D007167:Immunotherapy / Q000379:methods*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins