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Linker-based GnRH-PE chimeric proteins inhibit cancer growth in nude mice
A Ben-Yehudah1, S Yarkoni, A Nechushtan
1Department of Cellular Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract:
Since the number of cancer-related deaths has not decreased in recent years, major efforts are being made to find new drugs for cancer treatment. In this report we introduce the gonadotropin releasing hormone-Pseudomonas exotoxin (GnRH-PE) based chimeric proteins L-GnRH-PE66 and L-GnRH-PE40. These proteins are composed of a GnRH moiety attached to modified forms of Pseudomonas exotoxin via a polylinker (gly4ser)2. The chimeric proteins L-GnRH-PE66 and L-GnRH-PE40 have the ability to target and kill adenocarcinoma cell lines in vitro, whereas non-adenocarcinoma cell lines are not affected. We demonstrate that L-GnRH-PE66 and L-GnRH-PE40 efficiently inhibit cancer growth. Nude mice were injected subcutaneously with the SW-48 adenocarcinoma cell line to produce xenograft tumours. When the tumours were established and visible, the animals were injected with chimeric proteins for 10 days. At the end of this period, a reduction of up to 3-fold in tumor size was obtained in the treated mice, as compared with the control group, which received equivalent amounts of GnRH; the difference was even greater 13 days after termination of treatment. Thus, the chimeric proteins L-GnRH-PE66 and L-GnRH-PE40 are promising candidates for treatment of a variety of adenocarcinomas and their use in humans should be considered.
Insights
New chimeric proteins, gonadotropin-releasing hormone-Pseudomonas exotoxin (GnRH-PE) based L-GnRH-PE66 and L-GnRH-PE40, show promise in targeting and reducing adenocarcinoma tumor growth in preclinical models.
Area of Science:
- Oncology
- Biotechnology
- Molecular Biology
Background:
- Cancer mortality remains high, necessitating novel therapeutic strategies.
- Targeted drug delivery aims to improve cancer treatment efficacy.
- Gonadotropin-releasing hormone (GnRH) receptors are overexpressed on various cancer cells.
Purpose of the Study:
- To evaluate the efficacy of novel GnRH-Pseudomonas exotoxin (GnRH-PE) chimeric proteins, L-GnRH-PE66 and L-GnRH-PE40, as targeted cancer therapeutics.
- To assess the in vitro and in vivo anti-cancer activity of these chimeric proteins against adenocarcinoma cell lines.
Main Methods:
- Construction of GnRH-PE chimeric proteins (L-GnRH-PE66, L-GnRH-PE40) by linking GnRH moiety to modified Pseudomonas exotoxin.
- In vitro testing on adenocarcinoma and non-adenocarcinoma cell lines.
- In vivo xenograft tumor model in nude mice using SW-48 adenocarcinoma cells, followed by treatment with chimeric proteins.
Main Results:
- Chimeric proteins selectively targeted and killed adenocarcinoma cell lines in vitro.
- L-GnRH-PE66 and L-GnRH-PE40 demonstrated efficient inhibition of cancer growth.
- In vivo studies showed up to a 3-fold reduction in tumor size in treated mice compared to controls.
Conclusions:
- GnRH-PE chimeric proteins exhibit potent and selective anti-cancer activity against adenocarcinomas.
- These findings support the potential of L-GnRH-PE66 and L-GnRH-PE40 as novel therapeutic agents for adenocarcinoma treatment.
- Further clinical investigation in humans is warranted for these promising cancer therapies.