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A caspase-6 and anti-HER2 antibody chimeric tumor-targeted proapoptotic molecule decreased metastasis of human osteosarcoma.

Abstract
Human growth factor receptor-2 (HER2), overexpressed as a result of gene amplification, is detected in 20-40% of patients with breast, ovarian, endometrial, gastric, bladder, prostate, or lung cancers, correlated to metastasis of many tumors, and considered to be a poor prognostic indicator for these tumors. However, the data was controversial for HER2 overexpression and the prognosis of osteosarcoma, which is the most common primary malignant bone tumor, presents a therapeutic challenge in medical oncology due to its metastasis and poor response to current treatments. Previously, we reported that the immunocasp-6 gene fused by a HER2-specific single-chain antibody with domain II of Pseudomonas exotoxin A (PEA) and the 5' end of the truncated active caspase-6 could selectively suppress the HER2-positive tumor growth. In this study, we extend its application. We first confirmed the higher HER2 expression on the surface of metastatic osteosarcoma SOSP-9607(E10) cells, which then be proved specifically addicted to immunocasp-6-induced cells killing in vitro. Thereafter, the efficacy of immunocasp-6 was tested in an osteosarcoma lung metastasis mouse model using intramuscular (i.m.) injections of liposome-encapsulated vectors. Our results showed that the expression of the immunocasp-6 gene not only significantly prolonged animal's survival, but also greatly inhibited tumor metastasis. Thereby, our strategy suggests an alternative approach to treating HER2/neu-positive osteosarcoma.
AuthorsLi-Feng Wang, Yong Zhou, Yan-Ming Xu, Xiu-Chun Qiu, Ben-Gen Zhou, Fang Wang, Hua Long, Xiang Chen, Tong-Tao Yang, Bao-An Ma, Qing-Yu Fan, An-Gang Yang
JournalCancer investigation (Cancer Invest) Vol. 27 Issue 7 Pg. 774-80 (Aug 2009) ISSN: 1532-4192 [Electronic] England
PMID19488908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Immunotoxins
  • Recombinant Fusion Proteins
  • immunocasp-6
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Caspase 6
Topics
  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Bone Neoplasms (pathology)
  • Caspase 6 (genetics)
  • Cell Line, Tumor (transplantation)
  • Genes, Synthetic
  • Genetic Therapy
  • Humans
  • Immunotoxins (genetics, therapeutic use)
  • Lung Neoplasms (prevention & control, secondary)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Sequence Data
  • Osteosarcoma (pathology, prevention & control, secondary)
  • Random Allocation
  • Receptor, ErbB-2 (immunology)
  • Recombinant Fusion Proteins (genetics, therapeutic use)
  • Transfection
  • Xenograft Model Antitumor Assays

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