Antitumor efficacy of viral therapy using genetically engineered Newcastle disease virus [NDV(F3aa)-GFP] for peritoneally disseminated gastric cancer.
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.
Song
Kyo Young
KY
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Wong
Joyce
J
Gonzalez
Lorena
L
Sheng
Gang
G
Zamarin
Dmitriy
D
Fong
Yuman
Y
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009522:Newcastle disease virus / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000379:methods*; D010534:Peritoneal Neoplasms / Q000473:pathology / Q000628:therapy; D010537:Peritoneum / Q000473:pathology*; D013274:Stomach Neoplasms / Q000473:pathology / Q000628:therapy
C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
Cancer Res. 1994 Dec 1;54(23):6017-21
7954437
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8203-8
16717196
J Mol Med (Berl). 2000;78(3):166-74
10868479
J Natl Cancer Inst. 1994 Aug 17;86(16):1228-33
8040891
Lancet. 1971 Oct 9;2(7728):825
4106650
J Surg Oncol. 2008 Sep 15;98(4):273-6
18726891
J Virol. 2003 Sep;77(17):9522-32
12915566
Cancer. 1991 Jan 1;67(1 Suppl):260-5
1984825
Surg Oncol Clin N Am. 2002 Jul;11(3):661-80
12487061
Cancer Lett. 2001 Oct 22;172(1):27-36
11595126
Gan No Rinsho. 1986 Aug;32(10):1203-9
2431172
Cancer Res. 2007 Sep 1;67(17):8285-92
17804743
Gastric Cancer. 2002;5(1):1-5
12021853
Cancer Treat Res. 2007;134:195-214
17633055
Oncology. 2000 Feb;58(2):96-107
10705236
J Surg Res. 1992 May;52(5):448-53
1619912
Mol Med. 1998 Dec;4(12):783-94
9990864
Ann Oncol. 2004 Sep;15(9):1344-7
15319239
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
J Virol. 2006 Jun;80(11):5145-55
16698995
Cancer Res. 2002 Nov 1;62(21):6070-9
12414631
Med Oncol Tumor Pharmacother. 1992;9(4):169-71
1342060
J Virol. 1994 Nov;68(11):7654-8
7933158
J Gastroenterol. 2008;43(4):256-64
18458840
Eur J Surg Oncol. 2008 Jan;34(1):36-41
17442532
J Natl Cancer Inst. 1999 Oct 20;91(20):1708-10
10528013
Oncology (Williston Park). 2002 Nov;16(11):1483-92; discussion 1495-7
12469927