HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector.
The objective of this research was to evaluate the efficacy of a recombinant nonviral vector for targeted delivery of a thymidine kinase (TK) suicide gene to xenograft SKOV-3 tumors. The vector was genetically engineered and used to condense the TK gene into particles of less than 100 nm. The nanoparticles were used to transfect and kill SKOV-3 cancer cells in combination with ganciclovir (GCV) in vitro. The results demonstrated that the vector could effectively kill up to 80% of the SKOV-3 cancer cells. In the next step, the ability of the vector to deliver the TK suicide gene to xenograft tumors of SKOV-3 was studied. The results demonstrated that the vector could transfect tumors and result in significant tumor size reduction during the period that GCV was administered. Administration of GCV for at least 3 weeks post transfection was of paramount importance. These results illustrate the therapeutic efficacy and application of a designed recombinant nonviral vector in cancer gene therapy.


BACKGROUND
A recombinant nonviral vector is used to deliver a suicide thymidine kinase gene under gancylovir control in vitro to SKOV-3 cancer cells with 70% efficiency. Follow on testing in a xenograft tumor demonstrated tumor reduction persisting for three weeks.
Wang
Yuhua
Y
Department of Pharmaceutical Sciences, Center for Integrated Biotechnology, Washington State University, Pullman, Washington, USA.
Canine
Brenda F
BF
Hatefi
Arash
A
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D024221:Antineoplastic Protocols; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D013937:Thymidine Kinase / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000998:Antiviral Agents; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir
J Gene Med. 2007 Apr;9(4):275-86
17397090
Chembiochem. 2003 Apr 4;4(4):286-98
12672108
Protein Sci. 2002 Sep;11(9):2267-72
12192082
Curr Gene Ther. 2001 May;1(1):123-36
12109135
Cancer Res. 2001 Apr 15;61(8):3330-8
11309289
Science. 1992 Jun 12;256(5063):1550-2
1317968
J Control Release. 2009 Sep 15;138(3):188-96
19379785
Cancer Res. 2001 Apr 1;61(7):3022-6
11306482
Protein Eng Des Sel. 2004 Aug;17(8):625-33
15381761
J Surg Res. 2007 Nov;143(1):189-94
17950092
Cancer Gene Ther. 2003 May;10(5):353-64
12719705
Nat Protoc. 2006;1(5):2315-9
17406473
Oncogene. 2005 Feb 10;24(7):1231-43
15592511
Int J Pharm. 2009 Mar 18;369(1-2):162-9
19038320
Mol Pharm. 2009 Jul-Aug;6(4):1100-9
19419197
Biochem J. 2004 Jan 1;377(Pt 1):159-69
14505488
Mol Ther. 2007 Jun;15(6):1042-52
17406342
J Control Release. 2009 Jan 19;133(2):154-60
18940210
Hum Gene Ther. 2000 Nov 20;11(17):2389-401
11096443
J Cell Sci. 1999 Jun;112 ( Pt 12):2033-41
10341220
Expert Opin Drug Deliv. 2010 Apr;7(4):497-512
20151849
Cancer Res. 2009 Jun 1;69(11):4791-9
19487291
J Control Release. 2009 Jul 1;137(1):46-53
19303038
Hum Gene Ther. 1998 May 1;9(7):1083-92
9607419
Hum Gene Ther. 2000 Jul 20;11(11):1569-76
10945770