Artikel
Neurokinin type 1-receptor-based targeting of glioblastoma multiforme with toxin-labelled substance P
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Autoren
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D. Cordier
- Department of Neurosurgery, University Hospital Basel, Switzerland; Pharmazentrum, University Basel, Switzerland
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M. Sailer
- Department of Neurosurgery, University Hospital Basel, Switzerland; Pharmazentrum, University Basel, Switzerland
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A. Gerber
- Pharmazentrum, University Basel, Switzerland
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L. Mariani
- Department of Neurosurgery, University Hospital Basel, Switzerland; Pharmazentrum, University Basel, Switzerland
| Veröffentlicht: | 28. April 2011 |
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Gliederung
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Objective: Local recurrence of glioblastoma multiforme (GBM) after standard treatment, i.e. surgery and radiochemotherapy, occurs in more than 90% of cases. Sufficient local tumor control positively correlates to improved survival. Neurokinin type 1-receptors (NK1-R) are overexpressed in GBM. In previous clinical trials, NK1-R overexpression has successfully been exploited by intratumoral injection of radiolabelled substance P (SP). However, the therapeutic effect of radiolabelled SP was difficult to predict despite proven NK1-R expression. Furthermore, radiopharmaceuticals carry substantial disadvantages. The presented study aims at the development of a non-radioactive, SP-based local therapeutic system and at the elucidation of the underlying therapeutic mechanism.
Methods: In this experimental study we examined nine established human GBM cell lines quantifying the expression levels of NK1-R by qRT-PCR and Western Blot, thereby discriminating between the full-length NK1-R-variant and the truncated NK1-R variant. The cell lines were exposed to toxin-SP-conjugates. Saporin and cholera-toxin were used as toxins. Cell survival and proliferation were quantified in a standardized photometric assay. Furthermore, we examine the intracellular translocation of the conjugates and their action on physiological NK1-R signalling.
Results: NK1-R were expressed in all GBM cell lines with a more than 12-fold difference in expression levels. Choleratoxin-SP remained without effect on cell proliferation in all cell lines. Saporin-SP exhibited a cytoreductive effect on six cell lines, with an impressive specific effect in one cell line. The level of NK1-R expression did not correlate with the cytoreductive effect. Predominant expression of full-length NK1-R seems to be a prerequisite for a specific cytoreductive effect, cell lines with predominant expression of truncated NK1-R responded unspecifically to saporin-SP.
Conclusions: Toxin-SP-conjugates may be promising candidates for effective local GBM treatment. Further analysis of permissive or inhibitory factors besides the expressed NK1-R subtype on the action of the toxin-SP-compounds is ongoing.
