Transcriptional regulatory regions of the survivin gene activate an exogenous suicide gene in human tumors and enhance the sensitivity to a prodrug.
Selective expression of a therapeutic gene in tumors contributes to the efficacy and the safety of cancer therapy. Regulatory regions of genes that are preferentially expressed in tumors have been examined. The regions of the survivin gene exhibited the greatest activity in human hepatocellular carcinoma cells. Deletion of the survivin regulatory region from the 5'-side demonstrated that the 0.5 kb and the 1.4 kb fragments possessed a strong promoter activity with relative tumor specificity. Human tumors transfected with the herpes simplex virus-thymidine kinase gene, that was powered by the survivin region, became susceptible to a prodrug, ganciclovir. Although survivin gene expression was up-regulated in the G2/M-phase of the cell cycle, taxol or vincristine treatment, which induce cell cycle arrest at the M-phase, did not enhance the transcriptional activity of the survivin promoter. These data collectively suggest that the survivin regulatory region induces the expression of an exogenous gene in tumors, but the transcriptional activity is not directly linked with M-phase induction.
Kawamura
Kiyoko
K
Division of Pathology, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
Yu
Ling
L
Tomizawa
Minoru
M
Shimozato
Osamu
O
Ma
Guangyu
G
Li
Quanhai
Q
Sato
Ayako
A
Yang
Yanling
Y
Suzuki
Takeo
T
Abdel-Aziz
Nashwa Mohamed
NM
Tagawa
Masatoshi
M
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D000077022:Survivin; D019098:Telomerase / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014750:Vincristine / Q000494:pharmacology
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011355:Prodrugs; D000077022:Survivin; D014750:Vincristine; D051546:Cyclooxygenase 2; D013937:Thymidine Kinase; C509186:TERT protein, human; D019098:Telomerase; D017239:Paclitaxel; D015774:Ganciclovir