title: Evidence that Cereport's ability to increase permeability of rat gliomas is dependent upon extent of tumor growth: implications for treating newly emerging tumor colonies.
abstract: Cereport (RMP-7) enhances delivery of chemotherapeutics into brain tumors by increasing the permeability of the glioma vasculature (i.e. , the blood-brain tumor barrier; BBTB). Its effect on brain tumors has consistently been more robust than that on normal brain. The present experiments tested the hypothesis that the ability of Cereport to increase the permeability of infiltrating glioma colonies increases as the glioma colonies develop, in situ. In an initial preliminary experiment, the significant and selective effects of Cereport in tumor tissue and brain surrounding tumor were verified using [(14)C]carboplatin as a marker, 8 days after implantation of 50,000 RG2 cells. A second preliminary experiment established that the number of tumor cells initially seeded influences the growth rate of the tumor mass. Tumors seeded with 50,000 cells were larger than those seeded with 25,000 cells 3, 5, and 8 days after implantation. Next, the hypothesis that the extent of tumor growth increases Cereport's effects on the BBTB was tested by measuring the concentration of radiolabeled carboplatin in the tumor when 50,000 cells were implanted 3, 8, or 13 days prior to the experiment. While a reliable, approximately twofold increase in carboplatin concentration was seen in the 8- and 13-day-old tumors, no significant effect of Cereport was observed in the tumors that developed only 3 days, in situ. Finally, another test of the hypothesis was made by comparing Cereport's effects on 8-day-old tumors initially seeded with either 50,000 or 25,000 cells (the latter producing a smaller, more slowly developing, tumor mass). Again, significantly higher carboplatin concentrations were seen with Cereport in the 50,000 cell tumors (greater than two-fold increase), compared to the smaller, more slowly developing, 25,000 cell tumors (<30% increase). The tumor and its vasculature were characterized in additional rats implanted with RG2 cells using CD-31, laminin, and bradykinin B(2) receptor immunocytochemistry. Intense B(2) receptor staining was observed on cells within the parenchyma of normal brain and tumor but not on the vasculature of tumor or brain. An extensive network of CD-31 and laminin staining was seen within and around the tumors in all groups, indicating relatively rapid and robust changes in vascularity in response to the gliomas. However, no consistent difference in vascularity between groups was observed to account for the uptake differences seen with Cereport. Collectively, these data offer initial preclinical empirical support for the hypothesis that Cereport's effects on tumor permeability increase as the tumor grows, which we further hypothesize is likely related to features of vascular development within the tumor independent of numbers or general morphology of vessels. If a similar phenomenon is shown to occur with infiltrating colonies from spontaneously forming gliomas in humans or from newly emerging metastases in brain, these data could impact the design and conduct of future trials using approaches intended to enhance delivery of chemotherapeutics through increased permeability of the tumor vascular barrier.
authors.affiliation: Alkermes, Inc., Cambridge, Massachusetts, 02139, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Bartus
authors.forename: P
authors.initials: P
authors.lastname: Snodgrass
authors.forename: R L
authors.initials: RL
authors.lastname: Dean
authors.forename: J H
authors.initials: JH
authors.lastname: Kordower
authors.forename: D F
authors.initials: DF
authors.lastname: Emerich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D016190:Carboplatin / Q000493:pharmacokinetics*; D002452:Cell Count; D016503:Drug Delivery Systems; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin