Adenovirus-mediated gene therapy specific for small cell lung cancer cells using a Myc-Max binding motif.
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.
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
K
K
Nishino
T
T
Osaki
T
T
Kumagai
T
T
Kijima
I
I
Tachibana
H
H
Goto
T
T
Arai
H
H
Kimura
T
T
Funakoshi
Y
Y
Takeda
Y
Y
Tanio
S
S
Hayashi
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D015152:Blotting, Northern; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D015774:Ganciclovir / Q000494:pharmacology; D015870:Gene Expression; D016259:Genes, myc / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007279:Injections, Subcutaneous; D007763:Lac Operon; D008111:Liver Function Tests; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010538:Peritonitis / Q000473:pathology; D011401:Promoter Regions, Genetic; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C499330:MAX protein, human; C067850:Myc associated factor X; D014157:Transcription Factors; C068422:Max protein, mouse; D013937:Thymidine Kinase; D015774:Ganciclovir