Nishino K, Osaki T, Kumagai T, Kijima T, Tachibana I, Goto H, Arai T, Kimura H, Funakoshi T, Takeda Y, Tanio Y, Hayashi S
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Int J Cancer. 2001 Mar 15;91(6):851-6. 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.
近期针对胸段癌症患者的基因治疗临床试验表明，这些治疗耐受性良好，副作用极小，并且我们需要进一步提高基因转移至靶癌细胞的特异性和效率。我们之前报道过，通过在Myc-Max反应元件（核心核苷酸序列，CACGTG）的控制下转导单纯疱疹病毒胸苷激酶（HSV-TK）基因，过表达myc的小细胞肺癌（SCLC）细胞系对更昔洛韦（GCV）变得具有选择性敏感性，并且这种构建体（MycTK）可用于开发针对化疗和放疗耐药的SCLC的新型治疗方法。我们在此报告一种含有Myc-Max结合基序的复制缺陷型腺病毒载体（AdMycTK）对SCLC细胞的体内抗肿瘤作用和安全性。用AdMycTK进行体外感染使过表达myc的SCLC细胞系对GCV的敏感性提高了63至307倍。在体内注射AdMycTK后再给予GCV，可显著抑制在无胸腺小鼠皮下或腹腔中建立的过表达myc的肿瘤的生长。另一方面，用AdMycTK感染对表达极低水平myc基因的细胞的体外GCV敏感性或其皮下肿瘤的生长均无显著影响。此外，与赋予HSV-TK基因强但非特异性表达的AdCATK治疗相比，我们未观察到该治疗有明显的副作用，包括体重减轻或生化异常。这些结果表明，AdMycTK/GCV疗法对肿瘤过表达myc家族癌基因的SCLC患者有效。
