Abstract
Peritoneal dissemination is a common and fatal clinical manifestation of gastric cancer with few effective therapies available. Natural Newcastle disease virus (NDV) has been shown to be an effective oncolytic agent, and recent advances now allow genetic manipulation of this virus to improve cancer killing and safety. This study was designed to investigate the effectiveness of a genetically engineered NDV in the treatment of peritoneally disseminated gastric carcinoma. NDV mutant virus containing a modified F cleavage site and insertion of enhanced green fluorescent protein (GFP), NDV(F3aa)-GFP, was tested in vitro against human gastric cancer cells by standard cytotoxicity at different multiplicities of infection. To test NDV(F3aa)-GFP in vivo in a peritoneal carcinomatosis gastric tumor model, MKN-74 human gastric cancer cells were injected intraperitoneally (IP) in severe combined immunodeficient mice. Mice were treated with NDV(F3aa)-GFP either once or multiple times after tumor challenge. Effective killing of MKN-74 cells by NDV(F3aa)-GFP was found in vitro. This cancer killing was dose-related and correlated with viral replication. GFP expression was a good marker of infection. The virus was also effective as an antitumor therapy in a peritoneal cancer model that simulates clinical disease. Half the animals treated with virus had no evidence of disease. Genetically engineered NDV [NDV(F3aa)-GFP] administered IP is an effective antitumor therapy against peritoneal carcinomatosis from human gastric cancer in a xenograft model, without significant toxicity. These data provide further rationale for clinical trials involving NDV for peritoneal carcinomatosis from gastric cancer.
Similar content being viewed by others
References
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108
Nakajima T (2002) Gastric cancer treatment guidelines in Japan. Gastric Cancer 5:1–5
Park CH, Song KY, Kim SN (2008) Treatment results for gastric cancer surgery: 12 years’ experience at a single institute in Korea. Eur J Surg Oncol 34:36–41
Okajima K, Yamada S (1986) Surgical treatment of far-advanced gastric cancer. Jpn J Cancer Clin 32:1203–1209
Sugarbaker PH, Yonemura Y (2000) Clinical pathway for the management of resectable gastric cancer with peritoneal seeding: best palliation with a ray of hope for cure. Oncology 58:96–107
Ajani JA, Ota DM, Jackson DE (1991) Current strategies in the management of locoregional and metastatic gastric carcinoma. Cancer 67:260–265
Donahue JM, Mullen JT, Tanabe KK (2002) Viral oncolysis. Surg Oncol Clin N Am 11:661–680
Nemunaitis J (2002) Live viruses in cancer treatment. Oncol Hunt 16:1483–1492
Park MS, García-Sastre A, Cros JF, Basler CF, Palese P (2003) Newcastle disease virus V protein is a determinant of host range restriction. J Virol 77:9522–9532
Nelson NJ (1999) Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91:1708–1710
Csatary LK (1971) Viruses in the treatment of cancer. Lancet 2(7728):825
Krishnamurthy S, Takimoto T, Scroggs RA, Portner A (2006) Differentially regulated interferon response determines the outcome of Newcastle disease virus infection in normal and tumor cell lines. J Virol 80:5145–5155
Reichard KW, Lorence RM, Cascino CJ, Peeples ME, Walter RJ, Fernando MB, Reyes HM, Greager JA (1992) Newcastle disease virus selectively kills human tumor cells. J Surg Res 52:448–453
Sergel-Germano T, McQuain C, Morrison TG (1994) Mutations in the fusion peptide and heptad repeat regions of the Newcastle disease virus fusion protein block fusion. J Virol 68:7654–7658
Park MS, Steel J, García-Sastre A, Swayne D, Palese P (2006) Engineered viral vaccine constructs with dual specificity: avian influenza and Newcastle disease. Proc Natl Acad Sci U S A 103:8203–8208
Vigil A, Park MS, Martinez O, Chua MA, Xiao S, Cros JF, Martínez-Sobrido L, Woo SL, García-Sastre A (2007) Use of reverse genetics to enhance the oncolytic properties of Newcastle disease virus. Cancer Res 67(17):8285–8292
Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J, Randlev B, Heise C, Uprichard M, Hatfield M, Rome L, Rubin J, Kirn D (2002) Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res 62(21):6070–6079
Lorence RM, Katubig BB, Reichard KW, Reyes HM, Phuangsab A, Sassetti MD, Walter RJ, Peeples ME (1994) Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54:6017–6021
Lorence RM, Reichard KW, Katubig BB, Reyes HM, Phuangsab A, Mitchell BR, Cascino CJ, Walter RJ, Peeples ME (1994) Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86:1228–1233
Phuangsab A, Lorence RM, Reichard KW, Peeples ME, Walter RJ (2001) Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett 172:27–36
Cassel WA, Murray DR (1992) A ten year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate. Med Oncol Tumor Pharmacother 9:169–171
Batliwalla FM, Bateman BA, Serrano D, Murray D, Macphail S, Maino VC, Ansel JC, Gregersen PK, Armstrong CA (1998) A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4:783–794
Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY (2004) A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol 15:1344–1347
Ohtsu A (2008) Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol 43:256–264
Ceelen WP, Påhlman L, Mahteme H (2007) Pharmacodynamic aspects of intraperitoneal cytotoxic therapy. Cancer Treat Res 134:195–214
Bozzetti F, Yu W, Baratti D, Kusamura S, Deraco M (2008) Locoregional treatment of peritoneal carcinomatosis from gastric cancer. J Surg Oncol 98:273–276
Bennett JJ, Kooby DA, Delman K, McAuliffe P, Halterman MW, Federoff H, Fong Y (2000) Antitumor efficacy of regional oncolytic viral therapy for peritoneally disseminated cancer. J Mol Med 78:166–174
Disclosure of potential conflict of interests
The authors declare no conflict of interests related to this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Song, K.Y., Wong, J., Gonzalez, L. et al. Antitumor efficacy of viral therapy using genetically engineered Newcastle disease virus [NDV(F3aa)-GFP] for peritoneally disseminated gastric cancer. J Mol Med 88, 589–596 (2010). https://doi.org/10.1007/s00109-010-0605-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-010-0605-6