Intravenous Cereport (RMP-7) Enhances Delivery of Hydrophilic Chemotherapeutics and Increases Survival in Rats with Metastatic Tumors in the Brain Dwaine F. Emerich, 1,3 Reginald L. Dean, 1 JoAnne Marsh, 1 Melissa Pink, 1 Denise Lafreniere, 1 Pamela Snodgrass, 1 and Raymond T. Bartus 1,2 Received April 18, 2000; accepted June 23, 2000 Purpose. The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. Methods. Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the hydro- philic (carboplatin) chemotherapeutic agents, as well as the large hydrophilic marker, 70 kDa dextran. Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorel- bine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone. Results. Cereport enhanced the uptake of carboplatin and dextran, but not paclitaxel or carmustine. The pattern of Cereport’s uptake effect with carboplatin revealed that Cereport selectively increased the proportion of highly permeable regions. Survival was significantly enhanced when Cereport was combined with either carboplatin, vi- norelbine, or gemcitabine, but not carmustine, compared to each chemotherapeutic agent alone. Conclusions. These data provide the first evidence that Cereport, or any receptor-mediated approach intended to enhance the permeabil- ity of the blood-brain tumor barrier, can increase the delivery hydro- philic drugs to metastatic tumors in the brain, increasing survival in tumor-bearing rats. KEY WORDS: blood-brain tumor barrier; bradykinin; brain metas- tases; carboplatin; carmustine; paclitaxel; vinorelbine; gemcitabine. INTRODUCTION Tumors that metastasize to the central nervous system represent one of the most devastating complications in pa- tients with systemic cancer. They account for the majority of newly diagnosed brain tumors, with as many as 170,000 cancer patients in the United States developing brain metastases an- nually. Twenty-five to fifty percent of these patients die as a result of neurological complications (1). Single brain metas- tases can often be treated with stereotaxic radiosurgery or a combination of surgical resection and radiotherapy, in cases of large tumors. While aggressive treatment may add several months to a year to patients lives, recurrence of the tumor or the presence of new brain metastases, most often lead to death within three to six months following recurrence (2). The contribution of chemotherapy to multi-modality treatment of brain metastatic disease remains controversial. Despite continual developments of new chemotherapeutic drugs, the treatment of brain metastatic tumors has not been impacted (3). At least one reason for the ineffectiveness of chemotherapy is the existence of the blood brain tumor bar- rier (BBTB) which inhibits diffusion of water-soluble com- pounds and large lipophilic compounds from the vessel lumen to the tumor interstitial space. Neuroradiology studies ((4)for a review), imaging studies (5) and electron microscopy (6,7) have all confirmed that the BBTB of brain metastatic tumors is generally leaky compared to the normal BBB. Nonetheless, many of the principle components of the barrier, including tight intracellular junctions, astrocytic processes and basal lamina (6,7), persist to form a barrier within the tumor vessels that produces a significant obstacle to the delivery of poten- tially valuable drugs to brain tumors. In principle, increasing the permeability of the BBTB during administration of chemotherapeutic drugs should al- low many existing hydrophilic drugs to gain access to the brain tumor, potentially providing significant patient benefit (8). Cereport® (RMP-7) is the first receptor agonist analog shown to increase permeability of the BBTB (9–12). Cereport is a bradykinin analog with a longer half-life and greater se- lectivity for the constituitively expressed bradykinin B2 re- ceptor (compared to bradykinin itself) (12–14). Studies with animal models of glioma have demonstrated that intravenous (i.v.) Cereport selectively increases uptake of chemothera- peutics into gliomas (15–17) and recent imaging studies using PET and CT in human glioma patients have confirmed Cere- port’s selectivity in glioma tissue (18–20). Despite the evidence for significant modulation of the glioma vascular barrier, no studies have examined the use of receptor-mediated modulation of the BBTB of metastatic tu- mors in the brain. Relative to glioma, the vasculature supply- ing metastatic tumors in the brain is generally considered more permeable (7,21–23), and its response to many vasoac- tive compounds also differs (24–26). It therefore remains an open question as to whether Cereport (or any other receptor- mediated method of increasing BBTB permeability) can in- crease uptake of chemotherapeutic agents into metastatic tu- mors in the brain. For this reason, a series of experiments were conducted in a rat metastatic brain tumor model to (1) determine the ability of Cereport to enhance uptake of mul- tiple hydrophobic and hydrophilic compounds, (2) examine in greater detail the nature of the uptake effects achieved with carboplatin, and finally (3) determine whether Cereport ex- tends the survival benefit of the chemotherapeutic agents car- boplatin, carmustine, vinorelbine, and gemcitabine. MATERIALS AND METHODS Subjects Male Fischer rats (N229, 170–220g; Taconic Farms, Germantown, NY) were housed in pairs in polypropylene cages with free access to food and water. All procedures were reviewed and approved by Alkermes’ Animal Care and Use 1 Alkermes, Inc.,Cambridge, Massachusetts. 2 Department of Pharmacology and Experimental Therapeutics, Tufts University Medical Center, Boston, Massachusetts. 3 To whom correspondence should be addressed at Department of Pharmacology, Alkermes, Inc., 64 Sidney Street, Cambridge, Mas- sachusetts 02139. (e-mail: dwaine.emerich@alkermes.com) Pharmaceutical Research, Vol. 17, No. 10, 2000 Research Paper 1212 0724-8741/00/1000-1212$18.00/0 © 2000 Plenum Publishing Corporation