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.

Abstract

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.

• Authors: Yohann Loriot, Pierre Mordant, Bob D Brown, Jean Bourhis, Jean-Charles Soria, Eric Deutsch
• Journal: Anticancer research (Anticancer Res) Vol. 30 Issue 10 Pg. 3869-78 (Oct 2010) ISSN: 1791-7530 [Electronic] Greece
• PMID: 21036697 (Publication Type: Journal Article)

Chemical References

• Oligonucleotides, Antisense
• Proto-Oncogene Proteins c-bcl-2
• Thionucleotides
• oblimersen

Topics

• Animals
• Apoptosis (drug effects, genetics, radiation effects)
• Carcinoma, Small Cell (genetics, metabolism, radiotherapy, therapy)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics, radiation effects)
• Combined Modality Therapy
• Female
• Humans
• Lung Neoplasms (genetics, metabolism, radiotherapy, therapy)
• Mice
• Mice, Nude
• Oligonucleotides, Antisense (genetics, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics)
• Thionucleotides (genetics, pharmacokinetics, pharmacology)
• Xenograft Model Antitumor Assays