TY - JOUR
T1 - Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells
AU - Horio, Yoshitsugu
AU - Hasegawa, Yoshinori
AU - Sekido, Yoshitaka
AU - Takahashi, Masahide
AU - Roth, Jack A.
AU - Shimokata, Kaoru
N1 - Funding Information:
We thank Dr. H. Saito (Nagoya University School of Medicine, Nagoya, Japan) for his encouragement throughout this study and Dr. Kwun M. Fong (The Prince Charles Hospital, Brisbane, Australia) for helpful advice and discussions. We are grateful to K. Shimamoto for her technical assistance. This work was supported by a grant-in-aid for COE Research and a grant-in-aid for Scientific Research (C) from the Ministry of Education, Science, Sports, and Culture of Japan.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.cgt.7700148
DO - 10.1038/sj.cgt.7700148
M3 - Article
C2 - 10811471
AN - SCOPUS:0034085044
SN - 0929-1903
VL - 7
SP - 537
EP - 544
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 4
ER -