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Clinical Immunology [S. M. F., K. A. W., G. N. A.], and Hematology [C. N. A., C. H. P.] Units, Department of Medicine, Department of Microbiology and Immunology [K. A. W., G. N. A.], and Cancer Center, Medical Oncology [C. N. A., G. N. A.], University of Rochester Medical School, Rochester, New York 14642; Department of Pathology, Tulane University Medical Center, New Orleans, Louisiana 70112 [S. M. F.]; Cellular Immunology (Section), National Cancer Institute Bethesda, Maryland 20892 [D. S. K.]; and Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts 01730 [F. L. M.]
Tumor cells expressing the herpes simplex virus thymidine kinase (HSV-TK) gene are sensitive to the drug ganciclovir (GCV). We demonstrate here that HSV-TK-positive cells exposed to GCV were lethal to HSV-TK-negative cells as a result of a "bystander effect." HSV-TK-negative cells were killed in vitro when the population of cultured cells contained only 10% HSV-TK-positive cells. The mechanism of this "bystander effect" on HSV-TK-negative cells appeared to be related to the process of apoptotic cell death when HSV-TK-positive cells were exposed to GCV. Flow cytometric and electron microscopic analyses suggested that apoptotic vesicles generated from the dying gene-modified cells were phagocytized by nearby, unmodified tumor cells. Prevention of apoptotic vesicle transfer prevented the bystander effect.
The toxic effect of HSV-TK-positive cells on HSV-TK-negative cells was reproduced in an in vivo model. A mixed population of tumor cells consisting of HSV-TK-positive and HSV-TK-negative cells was inoculated s.c. into mice. Regression of the tumor mass occurred when the inoculum consisted of as few as 10% HSV-TK-expressing tumor cells.
The bystander effect was also demonstrated in i.p. tumor studies. Initial experiments demonstrated that prolonged survival (>70 days) occurred when a mixture containing 50% HSV-TK-positive and 50% HSV-TK-negative cells was injected i.p. followed by GCV treatment. Further, survival was prolonged for mice with a preexisting HSV-TK-negative i.p. tumor burden by injecting HSV-TK-positive cells and GCV. These results suggest that genetic modification of tumor cells may be useful for developing cancer therapies.
1 Supported in part by USPHS Grants HL-18208, CA-53352, and PO1 CA-59311 and the United States Department of Veterans Affairs.
2 Present address: Department of Pathology, Tulane University Medical Center, 1430 Tulane Ave., New Orleans, LA 70112.
3 To whom requests for reprints should be addressed, at University of Rochester, Medical Center, 601 Elmwood Ave., Rochester, NY 14642.
Received 4/23/93. Accepted 8/25/93.
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