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Vascular protection by chloroquine during brain
tumor therapy with Tf-CRM107
Hagihara N, Walbridge S, Olson AW, Oldfield EH, Youle RJ
Biochemistry Section, Surgical Neurology Branch, National
Institute of Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, Maryland 20892, USA.
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.
PMID: 10667564 [PubMed - indexed for MEDLINE]
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