title: Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment.
abstract: Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Uchino
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Akiko
authors.initials: A
authors.lastname: Harada
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000628:therapy*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011991:Receptors, Virus / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D019076:Transgenes; D014779:Virus Replication / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011991:Receptors, Virus; D019098:Telomerase