Adenovirus‐mediated gene therapy specific for small cell lung cancer cells using a Myc‐Max binding motif

• Published in: International journal of cancer 2001-03, Vol.91 (6), p.851-856
• Main Authors: Nishino, Kazumi, Osaki, Tadashi, Kumagai, Toru, Kijima, Takashi, Tachibana, Isao, Goto, Hiroyuki, Arai, Toru, Kimura, Hiromi, Funakoshi, Toshiki, Takeda, Yoshito, Tanio, Yoshiro, Hayashi, Seiji
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; adenovirus; Animals; Antiviral Agents - pharmacology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Basic-Leucine Zipper Transcription Factors; Biological and medical sciences; Blotting, Northern; Carcinoma, Small Cell - enzymology; Carcinoma, Small Cell - genetics; Carcinoma, Small Cell - therapy; Cell Division - drug effects; Cell Division - physiology; DNA-Binding Proteins - genetics; Ganciclovir - pharmacology; Gene Expression; gene therapy; Genes, myc - genetics; Genetic Therapy - methods; Humans; Injections, Subcutaneous; Lac Operon; Liver Function Tests; lung carcinoma; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - therapy; Max protein; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Myc binding motif; myc family oncogenes; myc gene; Other treatments; Peritonitis - pathology; Promoter Regions, Genetic; recombinant adenoviral vector; small cell lung cancer; Thymidine Kinase - biosynthesis; Thymidine Kinase - genetics; Transcription Factors; Transfection; Treatment. General aspects; Tumor Cells, Cultured; Tumors; tumor‐specific promoter
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1120>3.0.CO;2-1

Recent clinical trials of gene therapy for patients with thoracic cancers have shown that these treatments were well tolerated with minimal side effects and that we need to further enhance specificity as well as efficiency of gene transfer to target cancer cells. We previously reported that myc‐overexpressing SCLC cell lines became selectively sensitive to ganciclovir (GCV) by transducing the herpes simplex virus thymidine kinase (HSV‐TK) gene under the control of the Myc‐Max response elements (a core nucleotide sequence, CACGTG) and that this construct (MycTK) could be utilized to develop a novel treatment against chemo‐radio‐resistant SCLC. We report here in vivo antitumor effects and safety of a replication‐deficient adenoviral vector containing the Myc‐Max binding motif (AdMycTK) on SCLC cells. In vitro infection with AdMycTK selectively rendered myc‐overexpressing SCLC cell lines 63‐ to 307‐fold more sensitive to GCV. In vivo injections with AdMycTK followed by GCV administration markedly suppressed the growth of myc‐overexpressing tumors established in the subcutis or in the peritoneal cavity of athymic mice. On the other hand, infection with AdMycTK did not significantly affect either in vitro GCV sensitivity of the cells expressing very low levels of the myc genes or the growth of their subcutaneous tumors. Moreover, we observed no apparent side effects of this treatment including body weight loss or biochemical abnormalities in contrast to the treatment with AdCATK that conferred strong but nonspecific expression of the HSV‐TK gene. These results suggested that AdMycTK/GCV therapy is effective on SCLC patients whose tumors overexpress myc family oncogenes. © 2001 Wiley‐Liss, Inc.