Cerebrovascular Effects and Tumor Kinetics after a Single Intratumoral Injection of Human Recombinant Interleukin-2 Alone or in Combination with Intravenous Chemotherapy in a Rat Model of Glioma

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Abstract
It is well documented that drug delivery into experimental and human brain tumors is limited by the variably intact blood-brain barrier (BBB) at the growing edge. The aim of the present investigation was to examine the histopathological changes that occur after a single intralesional injection of human recombinant interleukin-2 (rIL-2) into a growing glioma and determine whether the injection improved delivery of cytotoxic drug into the neuropil surrounding the site of lymphokine injection. Because an intracerebral injection of rIL-2 causes a temporary breakdown in the BBB, we hoped to enhance drug penetration into peritumoral areas of brain with an intact BBB by using the novel biomodulating effect of rIL-2 on the cerebral endothelial cells. The results demonstrated that an intralesional injection of 7.2 x 10(4) National Units rIL-2 on Day 7 after tumor inoculation did not accentuate the already increased cerebrovascular permeability produced by the glioma nor did rIL-2 trigger additional or aggravate neurological deficits in glioma-bearing rats. Before the administration of chemotherapy in vivo, the RT-2 glioma cells were tested for in vitro sensitivity by colorimetric assay. At 24 hours after exposure to either methotrexate (MTX), vincristine (VIN), or doxorubicin (DOX), no significant inhibition of metabolic activity was observed. In contrast, a timed pulsed of any drug for 5 minutes caused significant dose-dependent inhibition of RT-2 glioma cells at 48 hours to 5 days after drug administration. Animal models receiving an intralesional injection of rIL-2 followed 3 days later by an intravenous dose of 30 mg/kg MTX, 0.23 mg/kg VIN, or 10 mg/kg DOX demonstrated that only MTX combined with intralesional rIL-2 significantly inhibited intracranial proliferation of RT-2 glioma cells. Use of intralesional rIL-2 and intravenous chemotherapy, however, did not significantly increase survival in this animal model of glioma. These results show that the combination of cytotoxic drugs with intralesional rIL-2 can be safely applied in the management of glioma and may form a rational basis for additional pharmacological investigations of a wider assortment of chemotherapies in combination with rIL-2 for intracranial malignancies.