Tumor regression by combination antisense therapy against Plk1 and Bcl-2.
Increased expression of the cell proliferation-associated polo-like kinase 1 (PLK1) and apoptosis-associated BCL-2 genes has been observed in different human malignancies. Inhibition of cell proliferation and reactivation of apoptosis are basic principles in anticancer therapy. The efficiency of this approach is often limited by insuf-ficient targeting and delivery of anticancer drugs into the tumors. Phosphorothioate antisense oligodeoxynucleotides (ODNs) directed against PLK1 and BCL-2 were administered systemically via the tail vein into nude mice bearing A549, MDA-MB-435, and Detroit562 xenografts. To enhance tumor-specific uptake and to reduce systemic toxicity of antisense ODNs membrane electroporation transfer was applied in vivo. Northern and Western blot analyses were used to assess PLK1 and BCL-2 expression. Tumor mass was assessed after resection of tumors. All three cell lines and corresponding xenografts expressed high levels of PLK1 and were sensitive towards antisense PLK1 treatment. Antisense BCL-2 therapy was effective in tumors expressing high levels of BCL-2, but not in A549 cells and corresponding xenografts, which express low levels of BCL-2. Administration of antisense ODNs in a dose of 5 mg/kg, twice weekly during four weeks supported by the membrane electroporation transfer, eradicated 60-100% of the xenografted tumors. Antitumor effect in BCL-2 overexpressing MDA-MB-435 cells was synergistic for BCL-2 and PLK1 combination therapy. This study provides evidence that combined systemic administration of antisense ODNs against proliferation and pro- survival associated targets and in vivo electroporation of tumors represents a promising antitumor therapeutic approach.
Elez
Robert
R
Department of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany. robert.elez@uniklinik-saarland.de
Piiper
Albrecht
A
Kronenberger
Bernd
B
Kock
Martin
M
Brendel
Martin
M
Hermann
Eva
E
Pliquett
Uwe
U
Neumann
Eberhardt
E
Zeuzem
Stefan
S
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D015536:Down-Regulation; D018274:Electroporation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D013873:Thionucleotides / Q000235:genetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D016376:Oligonucleotides, Antisense; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; D000097869:Polo-Like Kinase 1