Midkine promoter-based adenoviral suicide gene therapy to midkine-positive pediatric tumor

A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the α-fetoprotein promoter

“…The MK promoter-mediated oncolytic adenovirus was not harmful to liver but killed MK-positive tumours (Adachi et al, 2000). These data suggested that MK promoter-based gene therapy could facilitate selective killing of HCC and keep surrounding noncancerous tissues undamaged.…”

“…Expression of the MK gene in human adult tissues is extremely low and restricted; however, the expression is upregulated in a number of human tumours particularly in gastrointestinal tumours including HCC (Aridome et al, 1995;Koide et al, 1999). The 5 0 upstream region of the MK gene was demonstrated to activate a suicide gene in MK-positive human tumours (Adachi et al, 2000;Miyauchi et al, 2001;Wesseling et al, 2001). In this study, we compared the usefulness of the AFP and the MK promoters for HCC treatment by examining the frequency of MK and AFP expression in human HCC specimens and the transcriptional activity of the promoters in HCC cell lines.…”

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas

“…46 Neuroendocrine or neuronal carcinoma-specific promoters have been tested and some examples are the rat calcitonin promoter for treatment of medullary thyroid carcinoma, 47,48 the gastrin releasing peptide promoter for treatment of SCLC 49 and the midkine promoter for treatment of neuroblastoma. 50,51 However, the major drawback to these neuronal promoter-enhancer elements is that they are active albeit at a much lower level in normal tissues such as the adrenal gland, lung and brain. In our approach, because of the unique regulatory pattern of the INSM1 promoter, it is inactive in normal tissues but highly active in the neuroendocrine tumors.…”

Enhanced growth suppression in esophageal carcinoma cells using adenovirus-mediated fusion gene transfer (uracil phosphoribosyl transferase and herpes simplex virus thymidine kinase)

“…This toxicity was possibly due to the high level of TK protein expression by AxCA.TK infection, as has been reported by others. 27 Because the cytotoxic effect of AxCA.UT was well regulated with GCV treatment and comparable to the cytotoxic effect of AxCA.TK, we decided that AxCA.UT vector was superior to AxCA.TK vector. A second limitation of our in vivo study is that controls to assess whether there is any differential effect of AxCA.UP compared to AxCA.UT in the absence of drug treatment were not performed.…”

“…Previous reports demonstrate that it is good strategy to control encoding genes with tumor-specific promoters such as CEA promoter 34 or Midkine promoter. 27 Replication -competent E1B -attenuated adenovirus vector ( ONYX -015 ), 35 which replicates selectively in tumor cells lacking normal p53 function, is also a good candidate for UT fusion gene delivery. Among recent cancer gene therapy reports, adenoviral -mediated p53 gene transfer is frequently used, together with cis -dichloro -diammineplatinum( II ) administration.…”