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Eradication of Growth of HER2-Positive Ovarian Cancer With Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate in Mouse Xenograft Model
  1. Lin Yu, PhD*,,
  2. Yuxi Wang*,
  3. Yuqin Yao, PhD*,
  4. Wenting Li*,
  5. Qinhuai Lai*,
  6. Jun Li*,
  7. Yongjun Zhou*,
  8. Tairan Kang, PhD*,
  9. Yongmei Xie, PhD*,
  10. Yangping Wu*,
  11. Xiangzhen Chen*,
  12. Cheng Yi, PhD*,,
  13. Lantu Gou, PhD*, and
  14. Jinliang Yang, PhD*,
  1. *State Key Laboratory of Biotherapy, and
  2. Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
  1. Address correspondence and reprint requests to Lantu Gou and Jinliang Yang, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, People’s South Rd 17, Chengdu 610041, China. E-mail: goulantu{at}gmail.com; jlyang01{at}163.com.

Abstract

Objective Ovarian cancer is 1 kind of a highly malignant gynecologic tumor, and current treatments have not achieved satisfactory effects. Human epidermal growth factor receptor 2 (HER2)–targeted therapies including trastuzumab and trastuzumab-DM1 (T-DM1) (antibody-cytotoxic drug conjugates) have been applied to treat HER2-overexpressing breast cancers in clinic. In the present study, we explored whether T-DM1 could effectively treat HER2-positive human ovarian carcinoma in vitro and in vivo.

Methods HER2 expressions of 6 ovarian cancer cell lines and 2 breast carcinoma cell lines were validated, and the binding capacity of T-DM1 to HER2-positive ovarian cancer SKOV3 cells were analyzed by flow cytometry. Nude mice bearing intraperitoneal and subcutaneous SKOV3 xenografts were used to investigate the antitumor effect of T-DM1.

Results High HER2 expressions in SKOV3 cell lines were detected. The binding capacity of T-DM1 to HER2-positive SKOV3 cells was in a similar manner comparing with trastuzumab. In vitro, T-DM1 showed strong growth inhibitory on SKOV3 cells, with IC50 values of 0.15 nmol/L. Nude mice bearing intraperitoneal and subcutaneous SKOV3 xenografts were used to investigate the antitumor effects of T-DM1 in vivo. In subcutaneous xenografts model, T-DM1 (30 mg/kg and 10 mg/kg) indicated significant anticancer effects. It is noteworthy that tumors were completely eradicated in the T-DM1 (30 mg/kg) group, and no regrowth was observed in a long time after the termination of the treatment. In the peritoneal xenograft model, tumor nodules in 3 of 7 mice were hardly observed in the abdominal cavity of mice after intraperitoneal injection of T-DM1 (30 mg/kg). At the same time, tumor nodules from the other 4 mice weighed on the average of only 0.07 g versus 1.77 g in control group.

Conclusions Our data showed that T-DM1 possessed promising antitumor effects on HER2-overexpressing ovarian cancer in mouse model, which provided valuable references for the future clinical trials.

  • HER2
  • Ovarian cancer
  • Antibody drug conjugates
  • Trastuzumab-DM1

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Footnotes

  • This study was supported by the National Natural Science Foundation of China (no. 30872742, no. 81071818, and no. 81372822) and the National Science and Technology Major Project of China (2012ZX09103301-030).

  • The authors declare no conflicts of interest.