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Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells
Robert Pawliuk1, Thomas Bachelot, Omar Zurkiya
1Division of Health Sciences & Technology, Harvard-MIT, Cambridge, Massachusetts 02139, USA.
Abstract:
Endostatin, a 20-kDa carboxy-terminal fragment of collagen XVIII, is the leading member of a class of physiologic inhibitors of angiogenesis with potent antitumor activity. Repeated subcutaneous administration of recombinant endostatin in mice led to permanent regression of established tumors to a microscopic dormant state and prompted the initiation of human clinical trials. However, a discrepancy remained unresolved: sustained tumor regression has only been observed with a non-soluble, precipitated form of recombinant endostatin produced in bacteria. To shed light on this question and establish a model of systemic anti-angiogenic gene therapy of cancer that may surmount obstacles in protein production and delivery, we transduced murine hematopoietic stem cells with a retrovirus encoding a secretable form of endostatin. Despite continuous, high-level secretion of endostatin in the vasculature of all transplanted mice, we detected neither inhibition of in vivo neoangiogenesis nor antitumor activity. Resolution of this paradox may come from human trials of endostatin now underway.
Insights
Recombinant endostatin showed antitumor effects, but a soluble form failed to inhibit tumor growth or angiogenesis in mice. Further research is needed to understand this paradox and its implications for cancer therapy.
Area of Science:
- Biochemistry
- Oncology
- Gene Therapy
Background:
- Endostatin, a collagen XVIII fragment, inhibits angiogenesis and has antitumor activity.
- Recombinant endostatin has shown promise in preclinical studies, leading to human trials.
- A discrepancy exists regarding the efficacy of soluble versus precipitated endostatin.
Purpose of the Study:
- To investigate the efficacy of systemically delivered, secretable endostatin via gene therapy.
- To establish a model for overcoming protein production and delivery challenges in anti-angiogenic therapy.
- To resolve the paradox of endostatin's variable antitumor activity.
Main Methods:
- Retroviral transduction of murine hematopoietic stem cells with endostatin gene.
- Continuous systemic delivery of secretable endostatin through transplanted stem cells.
- Monitoring of in vivo neoangiogenesis and antitumor activity in mice.
Main Results:
- High-level secretion of endostatin was achieved in the vasculature of transplanted mice.
- No significant inhibition of in vivo neoangiogenesis was observed.
- No substantial antitumor activity was detected.
Conclusions:
- Systemic delivery of secretable endostatin via gene therapy did not yield expected anti-angiogenic or antitumor effects.
- The form of endostatin (soluble vs. precipitated) significantly impacts its therapeutic efficacy.
- Further investigation into endostatin's mechanism and delivery is crucial for effective cancer treatment.