| FOR PROFESSIONALS: |
Neuro-OncologyBlood-Brain Barrier Program |
FOR PROFESSIONALS:Preclinical Research ProjectsDr. Neuwelt’s research interests have centered around the blood-brain barrier (BBB) and brain tumor therapy. In his initial VA Merit Review grant in 1978, Dr. Neuwelt predicted that manipulation of the BBB with transient osmotic shrinkage had the potential for a therapeutic role in brain tumor therapy. This hypothesis has been verified (Kraemer 2001), and the BBB disruption technique is now central to the preclinical and clinical research studies in the Neuwelt laboratory. Overall, Dr. Neuwelt’s research interests have centered around improving brain tumor therapy, reducing chemotherapy side effects, and improving brain tumor imaging. Dr. Neuwelt currently has a VA Merit review grant, three R01 research grants funded by the NINDS, and an R13 NIH meeting grant. Cancers in the brain are difficult to treat because of neurotoxicity, tumor resistance, and minimal delivery of potential therapies across the blood-brain barrier. We do basic science and preclinical studies of new approaches to delivery, efficacy, and imaging in primary and metastatic brain tumor models. Oregon Health & Science University (OHSU), Portland Veterans Affairs Medical Center (PVAMC) and the Department of Veterans Affairs have a significant financial interest in Adherex, a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by the OHSU Integrity Program Oversight Council and the PVAMC Conflict of Interest in Research Committee. Reducing Chemotherapy Side Effects:FIGURE 1:
Increasing chemotherapy dose intensity is problematic due to the toxic side effects of chemotherapy such as ototoxicity, mucositis, nephrotoxicity, and bone marrow toxicity. We are investigating the use of thiol chemoprotective agents to reduce these chemotherapy-induced side effects. Delayed administration of sodium thiosulfate (STS) protected against carboplatin-induced ototoxicity and cochlear hair cell loss in guinea pigs (Neuwelt 1996). In rats, N-acetylcysteine (NAC) reduced cisplatin-induced hearing changes, and also blocked nephrotoxicity and weight loss (Dickey 2003, manuscript in preparation). When NAC was administered via a new “aortic infusion” technique to increase bone marrow perfusion in conjunction with chemotherapy in rats, the magnitude of chemotherapy-induced bone marrow toxicity was reduced, even in the presence of buthionine sulfoximine (BSO) (Neuwelt, 2001). One impediment to clinical use of chemoprotective thiols is the potential to interfere with the anti-tumor activity of chemotherapy. In a new preclinical study we showed that an optimized chemoprotective regimen (pretreatment with NAC combined with delayed administration of STS) reduced hematological toxicity in the rat, but had no impact on BBBD-enhanced chemotherapy efficacy against rat intracerebral tumors (Neuwelt 2003, Submitted for publication; Figure 1). Negative interactions of thiols with anti-tumor efficacy were avoided by temporal and spatial separation of chemoprotectant and chemotherapy treatments by changing the route and timing of administration. The thiol chemoprotective agents may also be neuroprotective, as we have demonstrated a reduction in stroke volume when rats are pretreated IV with NAC for 60 minutes prior to a transient middle cerebral artery occlusion (Bago 2003, submitted for publication). This may be important in preventing CNS injury from surgical procedures such as so called "pump brain" seen after cardiac surgery. Improving brain tumor therapy:FIGURE 2:
Improved Brain Tumor Imaging:A major area of research in the Neuwelt preclinical labs involves new magnetic resonance (MR) imaging modalities to monitor brain tumor growth and anti-tumor efficacy, characterize tumor changes associated with gene activation, apoptosis, or necrosis, and evaluate delivery of therapeutic agents to brain and intracerebral tumors. Dextran coated superparamagnetic iron oxide MR agents, such as Combidex (Ferumoxtron 10) and Ferumoxytol (Advanced Magnetics, Inc.) have a long plasma half-life coupled with uptake by phagocytic cells. We showed that Feridex could be delivered across the BBB in rats, but then the particles bound to the basement membrane and did not actually enter the brain parenchyma (Muldoon 1999). This does not happen with Combidex due to a better dextran coating of the iron oxide particle. Conjugation of these iron particles to tumor-specific mAbs may be a way of diagnosing tumor type as well as clarifying tumor spread (Remsen 1996). Combidex provides imaging of brain tumors by a slow leak into the tumor and brain around tumor and uptake by trapping reactive cells in and around the tumor. These agents may also provide imaging of inflammatory brain lesions, in a rat model of stroke. BBB Program Research Grants:Opening
of the Blood-Brain Barrier to Antitumor agents (Javits
R37 NS044687)
Two-Compartment Models to Improve Brain Tumor
Therapy (RO1 NS033618)
CNS Gene Delivery and Imaging in Brain Tumor
Therapy (RO1 NS034608)
Studies of the Blood-brain Barrier and its
Manipulation (VA Merit Review)
Neuroprotective Effect of Erythropoietin on chemo- and radiotherapy-induced
toxicity (Roche Foundation for Anemia Research; Soussain PI)
Studies Directed Toward the Eradication of Brain Metastases
of Breast Cancer (DOD Center of Excellence; Pat Steeg PI; Neuwelt
PI on subcontract)
The Annual Blood-Brain Barrier Disruption Consortium Meeting
(R13 CA86959) The annual BBBD and neuro-oncology conference addresses the hypothesis that increased delivery of therapeutics in CNS malignancy can improve survival and quality of life without undue toxicity. The goals of the annual meeting are to review preclinical research advances, discuss the status of BBB clinical trials that are open to patient enrollment, and develop new multi-center clinical protocols. Current issues in brain tumor therapy and neurological research are also discussed. Pending BBB Program Research Grants:Nanoparticle MR imaging of BBB inflammation at high Tesla in CNS tumors
BBB PROGRAM PRECLINICAL LABORATORY PERSONNEL:Leslie L. Muldoon, Ph.D., Director of Research
Operations D. Thomas Dickey, DVM Ying-Jen (Jeffrey) Wu, Ph.D. Michael A. Pagel, B.A. Sheila R. Taylor, B.A. |
To
increase chemotherapy effectiveness we may improve delivery to tumor
by osmotic opening of the blood-brain barrier, or intra-tumor slow
infusion with convection. Intra-arterial delivery (carotid or vertebral
artery) can improve drug delivery to tumor by 10-fold, and osmotic
BBBD can increase delivery by 10-fold, resulting in 100-fold increase
in tumor concentrations of chemotherapeutic agents (Barnett 1995;
Neuwelt 1998). Further dose intensification may be achieved by enhancing
the activity of chemotherapeutics or increasing the susceptibility
of the tumor cells to chemotherapy toxicity by decreasing endogenous
glutathione concentrations, or by inhibiting enzymes which deactivate
chemotherapeutics. We are investigating the use of buthionine sulfoximine
(BSO), a glutathione synthesis inhibitor, and O6-Benzylguanine (BG),
which inhibits acetyl-guanine transferase, as mechanisms to improve
brain tumor therapy. Another approach is the use of chemotherapy
immunoconjugates or radioimmunoconjugates directed to tumor antigens.
We have shown that an antibody-doxorubicin conjugate (BR96-DOX) is
highly effective against rat brain tumors that express the LewisY
antigen recognized by the BR96 monoclonal antibody (Remsen 2000),
and this targeted cytotoxicity can be enhanced with radiotherapy
(Remsen 2001). Unfortunately, in tumors with heterogeneous antigen
expression, treatment with immunoconjugate results in out growth
of antigen-negative
tumor (Figure 2). Current studies are concentrating on mechanisms
to increase bystander killing of non-expressing tumor cells adjacent
to targeted cells (Neuwelt, in press, Neurosurgery, January, 2004).