Targeted gene therapy for breast cancer with truncated Bid.
We studied the efficiency of the proapoptotic factor tBid, targeted to tumor cells using the promoters of the hTERT, Survivin and Muc1 genes, in killing breast cancer cells. tBid is the active fragment of the proapoptotic protein Bid and is generated in response to death receptor activation. When placed under control of a strong CMV promoter, tBid was highly efficient in killing breast cancer cells. When expression of tBid was driven by tumor-specific promoters, the magnitude of killing was significant in cell lines with high levels of promoter activity. For successful gene therapy with targeted tBid, it is therefore crucial to be able to predict promoter activity prior to selection of the therapeutic construct. To test whether gene expression could serve as a predictor, we correlated expression of Survivin, hTERT and Muc1 genes with the activity of the corresponding promoters in a panel of breast cancer cell lines. Expression of the Muc1 gene correlated well with the activity of its promoter and the resultant tumor cell killing. For the hTERT and Survivin promoters, however, promoter activity did not correlate well with the expression of the corresponding genes. The implications and possible mechanism of these discrepancies are discussed.
Kazhdan
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I
Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center, San Antonio, TX 78229, USA. kazhdan@uthscsa.edu
Long
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L
Montellano
R
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Cavazos
D A
DA
Marciniak
R A
RA
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018396:Mucin-1; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D000077022:Survivin; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000951:Antigens, Neoplasm; D051023:BH3 Interacting Domain Death Agonist Protein; C107489:BIRC5 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; C060192:MUC1 protein, human; D008869:Microtubule-Associated Proteins; D018396:Mucin-1; D009077:Mucins; D009363:Neoplasm Proteins; D000077022:Survivin; D019098:Telomerase