Vascular protection by chloroquine during brain tumor therapy with Tf-CRM107.
نویسندگان
چکیده
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.
منابع مشابه
Calculation of the Equivalent Dose of the First and the Most Important Secondary Particles in Brain Proton Therapy by Monte Carlo Simulation
Introduction: Due to nuclear interactions between the tissues and high-energy protons, the particles, including neutrons, positrons, and photons arise during proton therapy. This study aimed at investigating the dose distribution of proton and secondary particles, such as positrons, neutrons, and photons using the Monte Carlo method. Material and Methods:<...
متن کاملEvaluation of the effective dose during PBFT for brain cancer: A Monte Carlo Study
Introduction: Recently, an approach exploiting the proton therapy biological enhancement by using Boron atoms injected inside a tumor, has been proposed. Three alpha particles with an average energy around 4MeV are emitted from the point of reaction between a proton and boron. In addition, the 719 keV prompt gamma emitted by the proton Boron fusion reactions can be used for on-...
متن کاملAn fMRI study of human visual cortex in response to spatiotemporal properties of visual stimuli
ABSTRACT Background: The brain response to temporal frequencies (TF) has been already reported, but with no study reported for different TF with respect to various spatial frequencies (SF). Materials and Methods: fMRI was performed by 1.5T GE-system in 14 volunteers during checkerboard, with TFs of 4, 6, 8 and 10Hz in low and high SFs of 0.5 and 8cpd. Results: Average percentage BOLD signa...
متن کاملContribution of host-derived tissue factor to tumor neovascularization.
OBJECTIVE The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study. METHODS AND RESULTS We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types o...
متن کاملP143: The Neuroprotective Effect of Chloroquine in Animal Model of Traumatic Brain Injury
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in young adults and children, and is a leading public health problem worldwide. In TBI, neurological impairment is caused by immediate brain tissue disruption (primary injury) and post‑injury cellular and molecular events (secondary injury) that exacerbate the primary neurological insult. However, the destructi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer research
دوره 60 2 شماره
صفحات -
تاریخ انتشار 2000