Regression of human mammary adenocarcinoma by systemic administration of a recombinant gene encoding the hFlex-TRAIL
1Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, is a new member of the TNF family. It can specifically induce apoptosis in a variety of human tumors. To investigate the possibility of employing the TRAIL gene for systemic cancer therapy, we constructed a recombinant gene encoding the soluble form of the human Flt3L gene (hFlex) at the 5' end and the human TRAIL gene at the 3' end. Such design allows the TRAIL gene product to be secreted into the body circulation. We have also demonstrated that the addition of an isoleucine zipper to the N-terminal of TRAIL greatly enhanced the trimerization of the fusion protein and dramatically increased its anti-tumor activity. The fusion protein reached the level of 16-38 microg/ml in the serum after a single administration of the recombinant gene by hydrodynamic-based gene delivery in mice. A high level of the fusion protein correlated with the regression of a human breast tumor established in SCID mice. No apparent toxicity was observed in the SCID mouse model. In addition, the fusion protein caused an expansion of the dendritic cell population in the C57BL/6 recipient mice, indicating that the hFlex component of the fusion protein was functional. Thus, the hFlex-TRAIL fusion protein may provide a novel approach, with the possible involvement of dendritic cell-mediated anti-cancer immunity, for the treatment of TRAIL-sensitive tumors.
Insights
A novel fusion protein, hFlex-TRAIL, effectively targets and eliminates tumors by inducing apoptosis. This cancer therapy approach shows promise with enhanced anti-tumor activity and potential immune system involvement.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis in various human tumors.
- Systemic cancer therapy using TRAIL gene delivery is under investigation.
Purpose of the Study:
- To develop a novel fusion protein for enhanced systemic cancer therapy.
- To evaluate the anti-tumor activity and safety of the hFlex-TRAIL fusion protein.
Main Methods:
- Constructed a recombinant gene encoding soluble human Flt3L (hFlex) and human TRAIL.
- Incorporated an isoleucine zipper to enhance TRAIL trimerization and activity.
- Administered the recombinant gene via hydrodynamic delivery in mouse models (SCID and C57BL/6).
Main Results:
- The hFlex-TRAIL fusion protein was secreted into circulation, reaching 16-38 microg/ml.
- Significant regression of human breast tumors in SCID mice was observed.
- No apparent toxicity was detected in SCID mice; dendritic cell expansion noted in C57BL/6 mice.
Conclusions:
- The hFlex-TRAIL fusion protein demonstrates potent anti-tumor activity and potential for systemic cancer therapy.
- The fusion protein's efficacy may involve dendritic cell-mediated anti-cancer immunity.
- This approach offers a novel treatment strategy for TRAIL-sensitive tumors.
