title: Antiangiogenic drugs synergize with a membrane macrophage colony-stimulating factor-based tumor vaccine to therapeutically treat rats with an established malignant intracranial glioma.
abstract: Combining a T9/9L glioma vaccine, expressing the membrane form of M-CSF, with a systemic antiangiogenic drug-based therapy theoretically targeted toward growth factor receptors within the tumor's vasculature successfully treated >90% of the rats bearing 7-day-old intracranial T9/9L gliomas. The antiangiogenic drugs included (Z)-3-[4-(dimethylamino)benzylidenyl]indolin-2-one (a platelet-derived growth factor receptor beta and a fibroblast growth factor receptor 1 kinase inhibitor) and oxindole (a vascular endothelial growth factor receptor 2 kinase inhibitor). A total of 20-40% of the animals treated with the antiangiogenic drugs alone survived, while all nontreated controls and tumor vaccine-treated rats died within 40 days. In vitro, these drugs inhibited endothelial cells from proliferating in response to the angiogenic factors produced by T9/9L glioma cells and prevented endothelial cell tubulogenesis. FITC-labeled tomato lectin staining demonstrated fewer and constricted blood vessels within the intracranial tumor after drug therapy. Magnetic resonance imaging demonstrated that the intracranial T9 glioma grew much slower in the presence of these antiangiogenic drugs. These drugs did not affect in vitro glioma cell growth nor T cell mitogenesis. Histological analysis revealed that the tumor destruction occurred at the margins of the tumor, where there was a heavy lymphocytic infiltrate. Real-time PCR showed more IL-2-specific mRNA was present within the gliomas in the vaccinated rats treated with the drugs. Animals that rejected the established T9/9L glioma by the combination therapy proved immune against an intracranial rechallenge by T9/9L glioma, but showed no resistance to an unrelated MADB106 breast cancer.
authors.affiliation: Diagnostic and Molecular Health Care Group, Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
authors.forename: Edward W B
authors.initials: EW
authors.lastname: Jeffes
authors.forename: Jian Gang
authors.initials: JG
authors.lastname: Zhang
authors.forename: Neil
authors.initials: N
authors.lastname: Hoa
authors.forename: Animesh
authors.initials: A
authors.lastname: Petkar
authors.forename: Christina
authors.initials: C
authors.lastname: Delgado
authors.forename: Samuel
authors.initials: S
authors.lastname: Chong
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.forename: Ramon
authors.initials: R
authors.lastname: Sanchez
authors.forename: Sakineh
authors.initials: S
authors.lastname: Khalaghizadeh
authors.forename: Tetyana
authors.initials: T
authors.lastname: Khomenko
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Knight
authors.forename: Reza
authors.initials: R
authors.lastname: Alipanah
authors.forename: Tuong-Vi
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Chirag
authors.initials: C
authors.lastname: Shah
authors.forename: Seema
authors.initials: S
authors.lastname: Vohra
authors.forename: Jing-Li
authors.initials: JL
authors.lastname: Zhuang
authors.forename: Jessie
authors.initials: J
authors.lastname: Liu
authors.forename: H Terry
authors.initials: HT
authors.lastname: Wepsic
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jadus
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology; D000078183:Oxindoles; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C117011:3-(4-dimethylamino-benzylidenyl)-2-indolinone; D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; D006131:Growth Inhibitors; D007211:Indoles; D007376:Interleukin-2; D008565:Membrane Proteins; D000078183:Oxindoles; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C022960:2-oxindole; D016173:Macrophage Colony-Stimulating Factor