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Systemic Bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice.

Abstract
Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP-1), is expressed in the majority of NPCs. LMP-1 upregulates antiapoptotic genes, including bcl-2, and Bcl-2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl-2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl-2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666-1 line, a stably infected NPC-derived line that co-expresses LMP-1 and Bcl-2. We have shown that G3139 treatment of C666-1 in vitro caused sequence-dependent suppression of Bcl-2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days x 5 doses) delayed engraftment and significantly inhibited growth of established C666-1 xenografts in SCID mice compared to control oligo-treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days x 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real-time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl-2 levels were significantly decreased in G3139-treated animals. Our studies have demonstrated that the Bcl-2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666-1, and in combination with CDDP, is curative in C666-1 NPC xenograft tumors in vivo. The sequence-dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl-2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC.
AuthorsJill Lacy, Regina Loomis, Susan Grill, Pavani Srimatkandada, Rocco Carbone, Yung-Chi Cheng
JournalInternational journal of cancer (Int J Cancer) Vol. 119 Issue 2 Pg. 309-16 (Jul 15 2006) ISSN: 0020-7136 [Print] United States
PMID16477627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright2006 Wiley-Liss, Inc.
Chemical References
  • DNA, Viral
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Thionucleotides
  • Viral Matrix Proteins
  • oblimersen
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Carcinoma (drug therapy, virology)
  • Cisplatin (pharmacology)
  • DNA, Viral (blood, isolation & purification)
  • Herpesvirus 4, Human (genetics, isolation & purification)
  • Mice
  • Mice, SCID
  • Nasopharyngeal Neoplasms (drug therapy, virology)
  • Thionucleotides (pharmacology)
  • Transplantation, Heterologous
  • Tumor Burden
  • Viral Load
  • Viral Matrix Proteins (isolation & purification)

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