4-(3'-Bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline: a novel quinazoline derivative with potent cytotoxic activity against human glioblastoma cells.

Abstract

The novel quinazoline derivative 4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154) exhibited significant cytotoxicity against U373 and U87 human glioblastoma cell lines, causing apoptotic cell death at micromolar concentrations. The in vitro antiglioblastoma activity of WHI-P154 was amplified > 200-fold and rendered selective by conjugation to recombinant human epidermal growth factor (EGF). The EGF-P154 conjugate was able to bind to and enter target glioblastoma cells within 10-30 min via receptor (R)-mediated endocytosis by inducing internalization of the EGF-R molecules. In vitro treatment with EGF-P154 resulted in killing of glioblastoma cells at nanomolar concentrations with an IC50 of 813 +/- 139 nM, whereas no cytotoxicity against EGF-R-negative leukemia cells was observed, even at concentrations as high as 100 microM. The in vivo administration of EGF-P154 resulted in delayed tumor progression and improved tumor-free survival in a severe combined immunodeficient mouse glioblastoma xenograft model. Whereas none of the control mice remained alive tumor-free beyond 33 days (median tumor-free survival, 19 days) and all control mice had tumors that rapidly progressed to reach an average size of > 500 mm3 by 58 days, 40% of mice treated for 10 consecutive days with 1 mg/kg/day EGF-P154 remained alive and free of detectable tumors for more than 58 days with a median tumor-free survival of 40 days. The tumors developing in the remaining 60% of the mice never reached a size > 50 mm3. Thus, targeting WHI-P154 to the EGF-R may be useful in the treatment of glioblastoma multiforme.

• Authors: R K Narla, X P Liu, D E Myers, F M Uckun
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 4 Issue 6 Pg. 1405-14 (Jun 1998) ISSN: 1078-0432 [Print] United States
• PMID: 9626456 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Quinazolines
• WHI P154
• Epidermal Growth Factor

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use, toxicity)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Epidermal Growth Factor (pharmacology)
• Glioblastoma (drug therapy, pathology)
• Humans
• Mice
• Mice, SCID
• Quinazolines (chemistry, therapeutic use, toxicity)
• Transplantation, Heterologous
• Tumor Cells, Cultured