title: 188Re-HYNIC-trastuzumab enhances the effect of apoptosis induced by trastuzumab in HER2-overexpressing breast cancer cells.
abstract: OBJECTIVE
  The development of radioimmunotherapy has provided an impressive alternative approach in improving trastuzumab therapy. However, the mechanisms of trastuzumab and radiation treatment combined to increase therapeutic efficacy are poorly understood. Here, we try to examine the efficacy of cytotoxicity and apoptosis induction for (188)Re-HYNIC-trastuzumab in cancer cell lines with various levels of Her2.
  
  
  METHODS
  Fluorescence flow cytometry was used to detect the alterations of apoptosis induction after (188)Re-HYNIC-trastuzumab treatment in two breast cancer cell lines with different levels of HER2 (BT-474 and MCF-7) and a colorectal carcinoma cell line (HT-29) for control.
  
  
  RESULTS
  Our results indicated that (188)Re-HYNIC-trastuzumab led to cell death of breast cancer cells specifically in HER2 level-dependent and radioactivity dose-dependent fashions. In BT-474 cells, 370 kBq/ml of (188)Re-HYNIC-trastuzumab enhanced the cytotoxicity to a level nearly 100-fold that of trastuzumab-alone treatment. The results also revealed that the mitochondria-dependent pathway attenuated irradiation-induced apoptosis in HER2-expressing breast cancer cells after (188)Re-HYNIC-trastuzumab treatment. In contrast, only after 48 h of (188)Re-HYNIC-trastuzumab treatment, BT-474 cells exhibited typical apoptotic changes, including exposure of phospholipid phosphatidylserine on the cell surface, or fragmented DNA formation, in a radioactivity dose-dependent manner.
  
  
  CONCLUSIONS
  Briefly, our study demonstrates that (188)Re-labeled HYNIC-trastuzumab not only enhances cell death in a radioactivity dose-dependent fashion, but may also prolong the effects of apoptosis involved with the mitochondria-dependent pathway in HER2-overexpressing breast cancer cells. It is possible that the (188)Re-HYNIC-trastuzumab treatment induced a second round of apoptosis to prolong the effects of cell kill in these cancer cells. These data revealed that (188)Re-HYNIC-trastuzumab has the potential for use as a therapeutic radiopharmaceutical agent in HER2-overexpressing breast cancer cell treatment.
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, P.O. BOX 3-27, No. 1000, Wenhua Rd., Jiaan Village, Longtan Township, Taoyuan, 32546, Taiwan, tylo@iner.gov.tw.
authors.forename: Tsai-Yueh
authors.initials: TY
authors.lastname: Luo
authors.forename: Po-Ching
authors.initials: PC
authors.lastname: Cheng
authors.forename: Ping-Fang
authors.initials: PF
authors.lastname: Chiang
authors.forename: Ting-Wu
authors.initials: TW
authors.lastname: Chuang
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Yeh
authors.forename: Wuu-Jyh
authors.initials: WJ
authors.lastname: Lin
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D006801:Humans; D006834:Hydrazines / Q000627:therapeutic use*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D009539:Nicotinic Acids / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012211:Rhenium / Q000627:therapeutic use*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D006834:Hydrazines; D009539:Nicotinic Acids; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D012211:Rhenium; D000068878:Trastuzumab; C120392:6-hydrazinopyridine-3-carboxylic acid; C508053:ERBB2 protein, human