title: Vascular protection by chloroquine during brain tumor therapy with Tf-CRM107.
abstract: Tf-CRM107 is a conjugate of transferrin and a point mutant of diphtheria toxin that selectively kills cells expressing high levels of the transferrin receptor. Tf-CRM107 has been infused intratumorally into patients with malignant brain tumors. Although approximately half of the patients exhibit tumor responses, patients receiving higher doses of Tf-CRM107 may develop magnetic resonance image (MRI) evidence of toxicity indicative of small vessel thrombosis or petechial hemorrhage. Consistent with these clinical results we found that intracerebral injection of Tf-CRM107 into rats at total doses > or =0.025 microg causes brain damage detectable by MRI and histology. To widen the therapeutic window of Tf-CRM107, we explored ways to prevent this damage to the vasculature. We reasoned that the vasculature may be protected to a greater extent than tumor from Tf-CRM107 infused into brain parenchyma by i.v. injection of reagents with low blood-brain barrier permeability that block the toxicity of Tf-CRM107. Chloroquine, a well-characterized antimalarial drug, blocks the toxicity of diphtheria toxin and Tf-CRM107. Systemic administration of chloroquine blocked the toxicity of Tf-CRM107 infused intracerebrally in rats and changed the maximum tolerated dose of Tf-CRM107 from 0.2 to 0.3 microg. Moreover, chloroquine treatment completely blocked the brain damage detected by MRI caused by intracerebral infusion of 0.05 microg of Tf-CRM107. In nude mice bearing s.c. U251 gliomas, chloroquine treatment had little effect on the antitumor efficacy of Tf-CRM107. Thus, chloroquine treatment may be useful to reduce the toxicity of Tf-CRM107 for normal brain without inhibiting antitumor efficacy and increase the therapeutic window of Tf-CRM107 for brain tumor therapy.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hagihara
authors.forename: S
authors.initials: S
authors.lastname: Walbridge
authors.forename: A W
authors.initials: AW
authors.lastname: Olson
authors.forename: E H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: R J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins / Q000627:therapeutic use* / Q000633:toxicity*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D018316:Gliosarcoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011916:Rats, Inbred F344; D014168:Transferrin / Q000627:therapeutic use* / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D000922:Immunotoxins; C404391:Tf-CRM107; D014168:Transferrin; D002738:Chloroquine