title: Combination of conditionally replicative adenovirus and standard chemotherapies shows synergistic antitumor effect in pancreatic cancer.
abstract: Due to devastating prognosis, novel therapies are needed for pancreatic cancer. We are in preparation for a human clinical trial of a conditionally replicative adenovirus (CRAd) we developed. While most patients in the target population are receiving either gemcitabine or 5-fluorouracil chemotherapy, the combination with CRAd has not yet been studied. This study was designed to evaluate combination therapies with CRAd and current standard chemotherapies in pancreatic cancer. When the combination therapy was tested in vitro, gemcitabine pretreatment showed a synergistic effect in two out of four cell lines whereas CRAd followed by gemcitabine exhibited a synergistic effect in one cell line. With 5-fluorouracil, pretreatment with 5-fluorouracil produced a synergistic effect in three cell lines whereas post-treatment was synergistic in only one cell line. These effects were not fully explained by either induction of cyclooxygenase (Cox) 2 activity or adenoviral receptors with chemotherapeutics. In in vivo analyses with Hs766T xenograft, 5-fluorouracil slightly improved the CRAd antitumor effect but it was not significant. Pretreatment with gemcitabine embodied a significant tumor reduction compared with single therapy with gemcitabine. The most significant antitumor effect occurred when tumors were treated with 5/3COX2CRAdF and subsequent gemcitabine (P = 0.001 vs gemcitabine alone, P = 0.012 vs 5/3COX2CRAdF alone) at day 12. In MIA Paca-2, pretreatments with either 5-fluorouracil or gemcitabine improved the CRAd therapeutic effect when administered before CRAd injection (P = 0.03 and P = 0.01, respectively). These experiments indicate the possible benefit of combination therapies, and thus it is not necessary to interrupt chemotherapeutics when receiving CRAd therapy.
authors.affiliation: The Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Nelson
authors.forename: Julia
authors.initials: J
authors.lastname: Davydova
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Masato
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic
chemical_list: D000970:Antineoplastic Agents; D051546:Cyclooxygenase 2
references.citation: Antivir Ther. 1996 Jan;1(1):9-20
references.pmid: 11322261
references.citation: Am J Surg. 2008 Apr;195(4):481-90
references.pmid: 18361926
references.citation: Nat Med. 2000 Aug;6(8):879-85
references.pmid: 10932224
references.citation: J Gastrointest Surg. 2005 Nov;9(8):1068-77; discussion 1077-9
references.pmid: 16269377
references.citation: Int J Cancer. 2002 Jan 20;97(3):386-92
references.pmid: 11774294
references.citation: BioDrugs. 2002;16(2):77-87
references.pmid: 11985481
references.citation: Gastroenterology. 2003 Oct;125(4):1203-18
references.pmid: 14517802
references.citation: J Am Coll Surg. 1999 Jul;189(1):1-7
references.pmid: 10401733
references.citation: Expert Opin Biol Ther. 2004 Aug;4(8):1241-50
references.pmid: 15268659
references.citation: Ann Oncol. 2006 May;17 Suppl 5:v17-19
references.pmid: 16807450
references.citation: Ai Zheng. 2004 Dec;23(12):1666-70
references.pmid: 15601557
references.citation: Int J Cancer. 1997 Nov 27;73(5):729-34
references.pmid: 9398054
references.citation: Oncologist. 2008 May;13(5):562-76
references.pmid: 18515741
references.citation: Mol Ther. 2004 Nov;10(5):967-72
references.pmid: 15509514
references.citation: Eur J Cancer. 1999 May;35(5):808-14
references.pmid: 10505043
references.citation: Anticancer Res. 2008 Mar-Apr;28(2B):1303-8
references.pmid: 18505070
references.citation: Mol Ther. 2001 Mar;3(3):385-94
references.pmid: 11273781
references.citation: Cancer Res. 2004 Jun 15;64(12):4319-27
references.pmid: 15205347
references.citation: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references.pmid: 18287387
references.citation: Antiviral Res. 1990 Oct-Nov;14(4-5):181-205
references.pmid: 2088205
references.citation: Mol Pharmacol. 1993 Nov;44(5):1070-6
references.pmid: 8246910
references.citation: Ann Oncol. 2006 May;17 Suppl 5:v7-12
references.pmid: 16807468
references.citation: Pharmacol Rev. 1995 Jun;47(2):331-85
references.pmid: 7568331