Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells

Yoshitsugu Horio, Yoshinori Hasegawa, Yoshitaka Sekido, Masahide Takahashi, Jack A. Roth, Kaoru Shimokata

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The infection of recombinant adenovirus expressing wild-type p53 (Ad- p53) to lung cancer cells that harbor mutant p53 genes improves their response to cis-diamminedichloroplatinum(II). In this study, we tested whether this improvement in response is also seen in wild-type p53 (wt-p53)- containing cancer cells and whether this phenomenon is universal with other commonly used chemotherapeutic agents, including etoposide, 7-ethyl-10- hydrocycamptothecin, paclitaxel, and docetaxel. Using a panel of 7 non-small cell lung cancer cell lines with wild-type (2) or abnormal (2 null, 3 point- mutated) p53, we examined in vitro cytotoxicity using a tetrazolium-based colorimetric assay (3-(4,5-diethylthiazoyl-2-yl-2,5-diphenyltetrazolium bromide assay) and analyzed the combined effects of Ad-p53 and chemotherapeutic agents using the isobologram method. Ad-p53 and DNA-damaging agents (cis-diamminedichloroplatinum(II), etoposide, and 7-ethyl-10- hydrocycamptothecin) showed synergistic effects in six of seven cell lines but additive effects against a p53-mutated cell line. In contrast, Ad-p53 showed additive effects with the antitubulin agents (paclitaxel and docetaxel) in all four of the cell lines tested. Furthermore, we examined this synergistic interaction between Ad-p53 and DNA-damaging agents by flow cytometric analysis and DNA fragmentation analysis. Both analyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by DNA-damaging agents in six of seven cell lines. Our results suggest that Ad- p53 may synergistically enhance the chemosensitivity of the majority of non- small cell lung cancers to DNA-damaging agents due to augmentation of apoptosis.

Original languageEnglish
Pages (from-to)537-544
Number of pages8
JournalCancer Gene Therapy
Volume7
Issue number4
DOIs
Publication statusPublished - 01-01-2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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