Combination bcl-2 antisense and radiation therapy for nasopharyngeal cancer

Clin Cancer Res. 2005 Nov 15;11(22):8131-44. doi: 10.1158/1078-0432.CCR-05-1266.


Purpose: A wide variety of tumors depend on the dysregulation of Bcl-2 family proteins for survival. The resulting apoptotic block can often provide a mechanism for resistance to anticancer treatments, such as chemotherapy and radiation. This current study evaluates the efficacy of combining systemically delivered Bcl-2 phosphorothioate antisense (Bcl-2 ASO) and radiation for nasopharyngeal cancer therapy.

Results: Antisense uptake was unaffected by 0, 3, or 6 Gy radiation. Radiation decreased the fraction of viable C666-1 cells to 60%, with a further decrease to 40% in combination with Bcl-2 ASO. Despite a modest in vitro effect, Bcl-2 ASO alone caused the regression of established xenograft tumors in mice, extending survival by 15 days in a C666-1 and by 6 days in a C15 model. The survival times for mice treated with both Bcl-2 ASO and radiation increased by 52 days in C666-1 and by 20 days in C15 tumors. This combination resulted in a more-than-additive effect in C666-1 tumors. Less impressive gains observed in C15 tumors might be attributable to higher expression of antiapoptotic Bcl-2 family proteins and limited drug distribution in the tumor. Retreatment of C666-1 tumors with the Bcl-2 ASO-radiation combination, however, was effective, resulting in mice surviving for >80 days relative to untreated controls.

Conclusions: Our results show that the Bcl-2 ASO and radiation combination is a highly potent therapy for nasopharyngeal cancer. Further examination of combination therapy with radiation and other Bcl-2 family-targeted anticancer agents in both preclinical and clinical settings is definitely warranted.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Blood Vessels / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Combined Modality Therapy
  • Female
  • Fluorescein-5-isothiocyanate / chemistry
  • Fluorescein-5-isothiocyanate / pharmacokinetics
  • Humans
  • Kidney / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Microscopy, Fluorescence
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / pathology
  • Nasopharyngeal Neoplasms / radiotherapy*
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacokinetics
  • Oligonucleotides, Antisense / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Radiation, Ionizing
  • Tissue Distribution
  • Treatment Outcome
  • Xenograft Model Antitumor Assays / methods


  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • Fluorescein-5-isothiocyanate