Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer

H. G. Van Der Poel, B. Molenaar, V. W. Van Beusechem, H. J. Haisma, R. Rodriguez, D. T. Curiel, W. R. Gerritsen

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Purpose: We evaluated the delivery and oncolytic potential of targeted replication competent adenoviruses in bladder cancer lines. Materials and Methods: Seven established human bladder cancer tumor lines (5637, SW800, TCCsup, J82, Scaber, T24 and 253J) were studied for the expression of integrins αvβ3, αvβ5, Coxsackievirus and adenovirus receptor, epidermal growth factor receptor (EGF-R) and epithelial cell adhesion molecule antigens using flow cytometry analysis. Bispecific single chain Fv fragments were used to target replication deficient luciferase reporter adenovirus to EGF-R (425-s11) or to epithelial cell adhesion molecule (C28-s11) antigens. Moreover, a fiber modified adenovirus targeting αv-integrins was studied. Replication competent serotype-5 adenoviruses attenuated to replicate specifically in retinoblastoma pRb (Ad5-d24) or p53 deficient (Ad5-d55K) cells were tested in vitro for oncolytic properties. Results: Low to absent Coxsackievirus and adenovirus receptor expression was found in 5 of the 7 tumor lines (SW800, J82, T24, 5637 and Scaber). EGF-R expression was found in all cell lines, whereas elevated epithelial cell adhesion molecule expression was seen in 3 (5637, Scaber and TCCsup), αvβ3-integrin was found in 1 (Scaber) and αvβ5-integrin was found in 3 (TCCsup, 253J and T24). EGF-R targeting using 425-s11 improved transgene expression in all cell lines from 2.1 to 12.5 times over nontargeted viruses. Epithelial cell adhesion molecule and integrin targeting was inferior to EGF-R targeting with a maximal increase in transgene expression of 2 times for epithelial cell adhesion molecule in 5637 cells and 1.6 times for integrin targeting in T24 cells. Comparison of the wild-type replication competent virus with conditionally replicating adenoviruses (Ad5-d55K and Ad5-d24) showed superior oncolytic activity for the latter 2 in all lines. Furthermore, improved cytotoxicity (29% to 33%) was obtained in 4 of the 7 lines after pre-incubation of Ad5-d24 with 425-s11. Conclusions: EGF-R directed bispecific single chain antibodies enhance adenovirus mediated transgene expression and oncolysis in bladder cancer lines.

Original languageEnglish (US)
Pages (from-to)266-272
Number of pages7
JournalJournal of Urology
Volume168
Issue number1
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

Keywords

  • Adenoviridae
  • Bladder
  • Bladder neoplasms
  • Cell adhesion molecules
  • Gene expression

ASJC Scopus subject areas

  • Urology

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