title: 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.affiliation: Department of Experimental Oncology, Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Narla
authors.forename: X P
authors.initials: XP
authors.lastname: Liu
authors.forename: D E
authors.initials: DE
authors.lastname: Myers
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C113888:WHI P154; D004815:Epidermal Growth Factor