Inhibition of human glioblastoma cell adhesion and invasion by 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) and 4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154).

Abstract

Glioblastoma multiforme is a highly invasive primary brain tumor with a disappointingly high local recurrence rate and mortality despite intensive multimodality treatment programs. Therefore, new agents that are capable of inhibiting the infiltration of normal brain parenchyma by glioblastoma cells are urgently needed. Here, we show that the novel quinazoline derivatives 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) and 4-(3'-bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154) are potent inhibitors of glioblastoma cell adhesion and migration. Specifically, both compounds inhibited at micromolar concentrations: (a) integrin-mediated glioblastoma cell adhesion to the extracellular matrix proteins laminin, type IV collagen, and fibronectin; (b) integrin-independent epidermal growth factor-induced adhesion of glioblastoma cells to poly-L-lysine-coated tissue culture plates; (c) fetal bovine serum-induced polymerization of actin and actin stress fiber formation as well epidermal growth factor-stimulated formation of focal adhesion plaques in serum-starved glioblastoma cells; and most importantly, (d) glioblastoma cell migration in in vitro assays of tumor cell invasiveness using tumor cell spheroids and/or Matrigel-coated Boyden chambers. Further preclinical development of WHI-P131 and WHI-P154 may provide the basis for the design of more effective adjuvant chemotherapy programs for glioblastoma multiforme.

• Authors: R K Narla, X P Liu, D Klis, F M Uckun
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 4 Issue 10 Pg. 2463-71 (Oct 1998) ISSN: 1078-0432 [Print] United States
• PMID: 9796979 (Publication Type: Journal Article)

Chemical References

• Actins
• Antineoplastic Agents
• Integrins
• Quinazolines
• WHI P131
• WHI P154
• Epidermal Growth Factor

Topics

• Actins (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Adhesion (drug effects)
• Epidermal Growth Factor (pharmacology)
• Glioblastoma (drug therapy, pathology)
• Humans
• Integrins (physiology)
• Neoplasm Invasiveness
• Quinazolines (pharmacology)
• Tumor Cells, Cultured