Adenovirus-mediated gene therapy specific for small cell lung cancer cellsusing a myc-max binding motif

Recent clinical trials of gene therapy for patients with thoracic cancers h ave shown that these treatments were well tolerated with minimal side effec ts and that we need to further enhance specificity as well as efficiency of gene transfer to target cancer cells. We previously reported that mycovere xpressing SCLC cell lines became selectively sensitive to ganciclovir (GCV) by transducing the herpes simplex virus thymidine kinase (HSV-TK) gene und er the control of the Myc-Max response elements (a core nucleotide sequence , CACGTG) and that this construct (MycTK) could be utilized to develop a no vel treatment against chemo-radio-resistant SOLO. We report here in vivo an titumor effects and safety of a replication-deficient adenoviral vector con taining the MycMax binding motif (AdMycTK) on SOLO cells. In vitro infectio n 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 affec t either in vitro GCV sensitivity of the cells expressing very low levels o f the myc genes or the growth of their subcutaneous tumors, Moreover, we ob served no apparent side effects of this treatment including body weight los s or biochemical abnormalities in contrast to the treatment with AdCATK tha t conferred strong but nonspecific expression of the HSV-TK gene. These res ults suggested that AdMycTK/GCV therapy is effective on SOLO patients whose tumors overexpress myc family oncogenes, (C) 2001 Wiley-Liss, Inc.