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.