Intralesional mitoxantrone biopolymer-mediated chemotherapy prolongs survival in rats with experimental brain tumors

The present study was designed to test the efficacy of intratumoral biopolymer-mediated mitoxantrone chemotherapy in the rat brain 9L glioma model. Mitoxantrone polymers were tested in vitro in 9L and C6 cell cultures for 10 days. Subsequently, adult Fisher 344 rats were implanted with 5 x 10(4) 9L glioma cells in the frontal region of the brain. In a first experiment, 2 days after cells inoculation, one group of rats were implanted with a biopolymer loaded with 4 mg of mitoxantrone at the tumor site. A second group of rats received drug-free biopolymers and served as controls. In a second experiment, rats were implanted with a biopolymer loaded with 2 mg of mitoxantrone. Another group of rats received 2 mg of mitoxantrone intraperitoneally. Controls received drug-free biopolymers. Rats were sacrificed as soon as they developed progressive neurological deficits. In the first experiment mean survival of mitoxantrone-treated rats was 10 +/- 2 vs. 15 +/- 2 days for the control group (P = 0.0003). Early morbidity was seen in 60%, and impaired wound healing was seen in 40% of the 4 mg mitoxantrone treated animals. In the second experiment mean survival of mitoxantrone-treated rats was significantly longer than that of the control group (P<0.0001) with 33 +/- 7 vs. 13.8 +/- 2 days for the control group. Only transient early morbidity (20%) was observed at this dose. All rats in the intraperitoneally mitoxantrone-treated group died within the first 4 days after injection. We conclude that controlled-release EVAc carriers deliver biologically active mitoxantrone in a sustained fashion. In vivo biopolymer-mediated mitoxantrone in loco chemotherapy can significantly prolong survival in rats with intracerebral 9L gliomas. Morbidity is mainly dose related, and can be reduced at acceptable levels without compromising the therapeutic effect.