Abstract | OBJECTIVE: METHODS: Cocultures of human glioblastoma spheroids (derived from three separate patients) and fetal rat brain aggregates were examined for infiltration using confocal microscopy, in the presence of 0 to 100 mumol/L genistein, a tyrosine kinase (TK) inhibitor, and 3 mumol/L tyrphostin A25, a specific EGFR-TK inhibitor. RESULTS: Infiltration (not attachment) was completely inhibited by genistein at 10 mumol/L, the IC20 for monolayer growth inhibition in two cell lines. Tyrphostin A25 at 3 mumol/L (the IC20 for monolayers) reduced invasion in a third cell line from 38.8 +/- 6.1% invasion-hour per hour (n = 5) to 2.9 +/- 1.2% invasion-hour per hour (n = 6) (P = 0.0002, two-tailed t test, 93% inhibition), and from 0.54 +/- 0.065% per hour (slope) to 0.028 +/- 0.018% per hour (P = 0.00001, 95% inhibition). Maximal percent invasion was reduced from 100 +/- 0 to 7.4 +/- 5.6% of the fetal rat brain aggregate. No change was detected in EGFR-associated tyrosine phosphorylation at those doses in monolayers by 32P immunolabeling, consistent with the known effects of low concentrations of TK inhibitors. An increase in expression of wild-type and truncated EGFR was demonstrated by Western blotting. Invasion was equally well inhibited by a monoclonal antibody to the high-affinity ligand binding domain of EGFR and not by antibody to an inactive domain. CONCLUSION: Our observations support the role of EGFR activation as a determinant by which glioblastoma invades normal brain tissue, and we show that invasion can be effectively inhibited at much lower concentrations of TK inhibitors than are necessary for growth suppression.
|
Authors | P L Penar, S Khoshyomn, A Bhushan, T R Tritton |
Journal | Neurosurgery
(Neurosurgery)
Vol. 40
Issue 1
Pg. 141-51
(Jan 1997)
ISSN: 0148-396X [Print] United States |
PMID | 8971836
(Publication Type: Journal Article)
|
Chemical References |
- Enzyme Inhibitors
- Isoflavones
- Nitriles
- Tyrphostins
- tyrphostin 25
- Genistein
- ErbB Receptors
- Protein-Tyrosine Kinases
|
Topics |
- Animals
- Brain
(pathology)
- Brain Neoplasms
(pathology)
- Cell Division
(drug effects)
- Cell Movement
(drug effects)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- ErbB Receptors
(antagonists & inhibitors, physiology)
- Genistein
- Glioblastoma
(pathology)
- Humans
- Isoflavones
(pharmacology)
- Microscopy, Confocal
- Neoplasm Invasiveness
- Nitriles
(pharmacology)
- Protein-Tyrosine Kinases
(antagonists & inhibitors, physiology)
- Rats
- Spheroids, Cellular
(drug effects, pathology)
- Tyrphostins
|