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.