The Bystander effect : tumor regression when a fraction of the tumor mass is genetically modified

• Published in: Cancer research (Chicago, Ill.) Ill.), 1993-11, Vol.53 (21), p.5274-5283
• Main Authors: FREEMAN, S. M, ABBOUD, C. N, WHARTENBY, K. A, PACKMAN, C. H, KOEPLIN, D. S, MOOLTEN, F. L, ABRAHAM, G. H
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Cell Line, Transformed; Chemotherapy; Female; Ganciclovir - toxicity; herpes simplex virus; Kirsten murine sarcoma virus; Medical sciences; Mice; Mice, Inbred BALB C; Microscopy, Electron; Pharmacology. Drug treatments; Retroviridae Infections - genetics; Retroviridae Infections - pathology; Sarcoma, Experimental - genetics; Sarcoma, Experimental - pathology; Sarcoma, Experimental - ultrastructure; Simplexvirus - enzymology; Simplexvirus - genetics; Thymidine Kinase - genetics; Tumor Virus Infections - genetics; Tumor Virus Infections - pathology
• ISSN: 0008-5472; 1538-7445

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.