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In vivo activities of acidic fibroblast growth factor-Pseudomonas exotoxin fusion proteins
C B Siegall1, S L Gawlak, D F Chace
1Bristol-Myers Squibb, Molecular Immunology Department, Seattle, Washington 98121.
Abstract:
Fibroblast growth factor receptors are highly expressed in a variety of cancer cells and activated vasculature. Using chimeric toxins targeted to cell-surface a FGF receptors, we have demonstrated specific cytotoxic activity to these cell types. These molecules, aFGF-PE40 and aFGF-PE40 KDEL, are fusion proteins containing acidic FGF and either a 40- or a 66-kDa binding defective form of Pseudomonas exotoxin, respectively. Both aFGF-toxin fusion proteins were able to inhibit protein synthesis in vitro in a variety of carcinoma cell lines. The half-life of aFGF-PE40 in serum was found to be 41 min when coadministered with heparin. Administration of aFGF-PE40 or aFGF-PE4E KDEL with heparin inhibits the growth of established KB and preestablished A431 epidermoid carcinoma xenografts in athymic mice. The antitumor activities of the two aFGF-toxin fusion proteins were equivalent against the KB tumor xenografts. While we were able to slow the growth of the KB tumor xenografts, we were unable to cause tumor regressions. Histochemical analysis of treated versus untreated tumor tissue revealed a difference in tumor size but not of vascularity. We conclude that aFGF-PE40 and aFGF-PE4E KDEL have in vivo antitumor activity that targets the tumor cell mass rather than vascular structures in mice xenografted with human epidermoid carcinoma.
Insights
Chimeric toxins targeting fibroblast growth factor receptors (FGFRs) showed cytotoxic activity against cancer cells. These FGFR-targeted toxins inhibited tumor growth in mice, indicating potential for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Fibroblast growth factor receptors (FGFRs) are overexpressed in various cancer cells and tumor vasculature.
- Targeting cell-surface receptors offers a strategy for cancer therapy.
Purpose of the Study:
- To evaluate the in vivo antitumor activity of chimeric toxins targeting FGFRs.
- To determine if these toxins target tumor cells or tumor vasculature.
Main Methods:
- Development of chimeric toxins: acidic FGF fused to Pseudomonas exotoxin (aFGF-PE40, aFGF-PE40 KDEL).
- In vitro assessment of protein synthesis inhibition in carcinoma cell lines.
- In vivo studies using KB and A431 epidermoid carcinoma xenografts in athymic mice, with coadministration of heparin.
- Histochemical analysis of tumor tissue.
Main Results:
- aFGF-PE40 and aFGF-PE40 KDEL demonstrated specific cytotoxic activity and inhibited protein synthesis in vitro.
- Co-administration with heparin increased the half-life of aFGF-PE40.
- Both toxins inhibited the growth of established KB and A431 xenografts but did not cause regression.
- Histochemical analysis showed reduced tumor size but no change in vascularity.
Conclusions:
- Chimeric toxins targeting FGFRs exhibit in vivo antitumor activity against human epidermoid carcinoma xenografts in mice.
- The antitumor effect primarily targets the tumor cell mass, not the tumor vasculature.