This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by Halldén, G. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by Halldén, G.

A Novel Assay to Assess Primary Human Cancer Infectibility by Replication-Selective Oncolytic Adenoviruses

¹ Cancer Research UK Molecular Oncology Unit, Imperial School of Medicine and ² Department of Obstetrics and Gynaecology, Hammersmith Hospital, London, United Kingdom; ³ Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, California; ⁴ Department of Clinical Pharmacology, Oxford University Medical School, Oxford, United Kingdom; and ⁵ Jennerex Biotherapeutics, Mill Valley, California

Requests for reprints: Gunnel Halldén, Cancer Research UK Molecular Oncology Unit, Barts and the London School of Medicine and Dentistry, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-207-014-0426; Fax: 44-207-014-0431; E-mail: Gunnel.Hallden{at}cancer.org.uk..

Purpose: Replication-selective oncolytic adenoviruses hold promise for cancer treatment, but the predictive use of cell lines, dissociated tumor tissue, and animal models for efficacy against primary cancers are unclear. To further evaluate cytotoxicity and the potential for efficacy of replication-competent adenoviruses we therefore developed a novel methodology using primary human cancer specimens ex vivo; ovarian, colon, rectal, and breast carcinomas were included.

Experimental Design: Tissue culture conditions were developed to maintain viability of adenocarcinomas ex vivo for 48 hours postsurgery. Explants were infected by replication-competent (wild type 5 and E1A mutant dl922-947) and replication-defective (dl312) adenoviruses; early (E1A) and late (hexon) viral gene expression, _v integrins, coxsackievirus and adenovirus receptor (CAR) and tissue viability were assessed by immunohistochemistry and histopathology. Viral replication was verified by replication assays on selected samples.

Results: Viral gene expression varied dramatically among cancer specimens (n = 41). With Ad5, hexon expression was high in 8 of 11 tested specimens, whereas E1A levels were detectable in 16 of 27 tumor explants. Viral gene expression, distribution, and cytopathic effects were greater postinfection with dl922-947. Specimens that supported early gene expression (E1A) also supported viral replication in 13 of 14 tested cases, determined by recovery of infectious units. As predicted, the replication-defective adenovirus dl312 was not associated with viral gene expression.

Conclusions: Primary human tumor tissue remained viable when cultured ex vivo enabling evaluation of viral mutants in tissue with intact morphology. This assay may have great use in determining treatment-sensitive cancers and assess specific oncolytic mutants in individual cases.

Key Words: adenocarcinoma • deletion mutants • ex vivo • preclinical models • gene therapy

This article has been cited by other articles:

				I. Peerlinck, S. Amini-Nik, R. K. Phillips, R. Iggo, N. R. Lemoine, S. Tejpar, and G. Vassaux Therapeutic Potential of Replication-Selective Oncolytic Adenoviruses on Cells from Familial and Sporadic Desmoid Tumors Clin. Cancer Res., October 1, 2008; 14(19): 6187 - 6192. [Abstract] [Full Text] [PDF]

				K. Gaballah, A. Hills, D. Curiel, G. Hallden, P. Harrison, and M. Partridge Lysis of Dysplastic but not Normal Oral Keratinocytes and Tissue-Engineered Epithelia with Conditionally Replicating Adenoviruses Cancer Res., August 1, 2007; 67(15): 7284 - 7294. [Abstract] [Full Text] [PDF]

				Q. Zhang, G. Chen, L. Peng, X. Wang, Y. Yang, C. Liu, W. Shi, C. Su, H. Wu, X. Liu, et al. Increased safety with preserved antitumoral efficacy on hepatocellular carcinoma with dual-regulated oncolytic adenovirus. Clin. Cancer Res., November 1, 2006; 12(21): 6523 - 6531. [Abstract] [Full Text] [PDF]

				Y. Li, N. Idamakanti, T. Arroyo, S. Thorne, T. Reid, S. Nichols, M. VanRoey, G. Colbern, N. Nguyen, O. Tam, et al. Dual Promoter-Controlled Oncolytic Adenovirus CG5757 Has Strong Tumor Selectivity and Significant Antitumor Efficacy in Preclinical Models Clin. Cancer Res., December 15, 2005; 11(24): 8845 - 8855. [Abstract] [Full Text] [PDF]