Inhibition of BCL-2 in small cell lung cancer cell lines with oblimersen, an antisense BCL-2 oligodeoxynucleotide (ODN): in vitro and in vivo enhancement of radiation response

Background: Oblimersen, an ODN targeting Bcl-2 RNA, has been shown to be effective in reducing Bcl-2 expression in vitro and in in vivo models engineered to overexpress Bcl-2. The present study evaluated the efficacy of combining Bcl-2 ODN and radiation in small-cell lung cancers (SCLC) cell lines.

Materials and methods: The in vitro effect was determined using short term (cell viability) and long term (clonogenic) assays. Apoptosis, Bcl-2 expression and intratumoural uptake of the FAM-ODN with or without prior radiation treatment were also evaluated. Combination of ODN and RT was also assessed in vivo.

Results: Radiation was shown to increase intracellular and intratumoural penetration of oblimersen, confirming previous results obtained in prostate Cancer xenograft models. Oblimersen decreased Bcl-2 protein expression in vitro and in vivo. Bcl-2 ODN sensitised H69 cells to radiation in vitro and in vivo. Oblimersen increased radiation-induced Apoptosis and decreased in vivo tumoural vascularisation.

Conclusion: Oblimersen was shown to increase in vitro and in vivo effect of RT on SCLC cell lines. Radiation increases intracellular and intratumoural penetration of ODN. This pre-clinical study argues in favour of clinical development in localised SCLC.