Treatment of HER2-expressing breast cancer and ovarian cancer cells with alpha particle-emitting 227Th-trastuzumab

Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):563-70. doi: 10.1016/j.ijrobp.2010.08.038.

Abstract

Purpose: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate (227)Th-p-isothiocyanato-benzyl-DOTA-trastuzumab ((227)Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of (227)Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene.

Methods and materials: Clonogenic survival and cell growth rates of breast cancer cells treated with (227)Th-trastuzumab were compared with rates of cells treated with nonbinding (227)Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated.

Results: SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml (227)Th-trastuzumab for 1 h at 4°C, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines.

Conclusions: Clinically relevant activity concentrations of (227)Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of (227)Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with (227)Th-trastuzumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived / pharmacokinetics
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Apoptosis / radiation effects*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • Cell Proliferation / radiation effects
  • Cell Survival / radiation effects*
  • Female
  • Genes, erbB-2*
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use*
  • Neoplasm Proteins / metabolism
  • Organometallic Compounds / pharmacokinetics
  • Organometallic Compounds / therapeutic use*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / radiotherapy*
  • Radiotherapy Dosage
  • Receptor, ErbB-2 / metabolism
  • Relative Biological Effectiveness
  • Rituximab
  • Trastuzumab
  • Tumor Stem Cell Assay / methods

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived
  • Immunoconjugates
  • Neoplasm Proteins
  • Organometallic Compounds
  • thorium-227-DOTA-rituximab
  • thorium-227-p-isothiocyanato-benzyl-DOTA-trastuzumab
  • Rituximab
  • Receptor, ErbB-2
  • Trastuzumab