A caspase-6 and anti-HER2 Antibody Chimeric Tumor-Targeted Proapoptotic Molecule Decreased Metastasis of Human Osteosarcoma

Cancer Invest. 2009 Aug;27(7):774-80. doi: 10.1080/07357900802427935.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Bone Neoplasms / pathology*
  • Caspase 6 / genetics
  • Cell Line, Tumor / transplantation
  • Genes, Synthetic
  • Genetic Therapy
  • Humans
  • Immunotoxins / genetics
  • Immunotoxins / therapeutic use*
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Sequence Data
  • Osteosarcoma / pathology
  • Osteosarcoma / prevention & control
  • Osteosarcoma / secondary*
  • Random Allocation
  • Receptor, ErbB-2 / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / therapeutic use*
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • Immunotoxins
  • Recombinant Fusion Proteins
  • immunocasp-6
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Caspase 6