1998 Abstract: INFLUENCE OF p53 STATUS ON THE EFFICACY OF HSV-MEDIATED CANCER GENE THERAPY. S.S. Yoon, N.M. Carroll, E.A. Chiocca, K.K. Tanabe. Dept. of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 21
Abstracts 1998 Digestive Disease Week
#1073
INFLUENCE OF P53 STATUS ON THE EFFICACY OF HSV-MEDIATED CANCER GENE THERAPY. S.S. Yoon, N.M. Carroll, E.A. Chiocca, K.K. Tanabe. Dept. of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Herpes simplex virus type 1 (HSV) is an ideal agent for cancer gene therapy. Cellular infection with HSV leads to viral replication, cellular disruption, and production of progeny virion. We have previously demonstrated that treatment of colon carcinomas with HSV results in significant anti-tumor effects in animal models. Over 60% of colon carcinomas have p53 mutations, which play a role in tumor cell resistance to chemotherapy and radiation therapy. In the present study we have examined whether tumor cell p53 status influences HSV-mediated cytotoxicity. Methods: hrR3 is a recombinant HSV vector that has significant anti-tumor activity in vivo. KOS is a wildtype HSV strain. SAOS-2 cells are p53-null and have been transfected with several p53 constructs: SAOS-2-WT1 and SAOS-2-WT2 clones express wildtype p53; SAOS-2-mut143, SAOS-2-mut175, and SAOS-2-mut24 clones express mutant forms of p53. Each HSV vector was added to the SAOS-2 transfectants using several multiplicities of infection (MOI), and cell survival was quantitated 6 days later using MTT. Results: Each of the SAOS-2 transfectants were susceptible to the lytic effects of both hrR3 and KOS HSV replication (Figure). p53 mutant cell lines were not resistant to HSV-mediated cytotoxicity.
Conclusion: HSV vectors are extremely cytotoxic to human tumor cells, even when used at infection rates as low as one viral particle per 10 tumor cells (MOI = 0.1). Although p53 mutations are prevalent in colon carcinomas and may lead to resistance to chemotherapy and radiation therapy, p53-mutant cells are as susceptible to HSV-mediated cytotoxicity as p53-wildtype cells. These results provide additional rationale for application of HSV-based gene therapy against colon carcinomas.
Copyright 1996 - 1998, SSAT, Inc. Revised 29 June 1998.
