We describe a technique for the treatment of malignant brain tumors based on local delivery of the anti-angiogenic protein endostatin from genetically engineered cells encapsulated in ultrapure sodium alginate. Alginate consists of L-guluronic and D-mannuronic acid, which in the presence of divalent cations forms an extended gel network, in which cells reside and remain immunoisolated, when implanted into the rat brain. Here, we show that endostatin-transfected cells encapsulated in alginate maintain endostatin secretion for at least four months after intracerebral implantation in rats. During the implantation period 70% of the encapsulated cells remained viable, as opposed to 85% in in vitro-cultured capsules. Rats that received transplants of BT4C glioma cells, together with endostatin-producing capsules (0.2 microg/ml per capsule), survived 84% longer than the controls. The endostatin released from the capsules led to an induction of apoptosis, hypoxia, and large necrotic avascular areas within 77% of the treated tumors, whereas all the controls were negative. The encapsulation technique may be used for many different cell lines engineered to potentially interfere with the complex microenvironment in which tumor and normal cells reside. The present work may thus provide the basis for new therapeutic approaches toward brain tumors.

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Radiation during deep inspiration allows loco-regional treatment of left breast and axillary-, supraclavicular-and internal mammary lymph nodes without compromising target coverage or dose restrictions to organs at risk, Acta Oncologica, 51:3, 333-344,

Liposomal drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free drug. The therapeutic index may be improved further by combining cytotoxic drugs and radiotherapy. Successful therapy requires that the cytotoxic agents reach the tumor cells. Therefore, we studied tumor growth and the microdistribution of liposomal doxorubicin (Caelyx) with and without additional ionizing radiation in human osteosarcoma xenografts in athymic mice. Caelyx was injected i.v. 1 day before single or fractionated radiotherapy. Both chemoirradiation regimens induced significant tumor growth delays and worked synergistically. Confocal laser scanning microscopy showed that intact liposomes were located in close proximity to endothelial cells, and the distribution of released doxorubicin was heterogeneous. Before radiotherapy, hardly any doxorubicin was localized in the central parts of the tumor. Radiotherapy increased the tumor uptake of doxorubicin by a factor of two to four, with drug being redistributed farther from the vessels in the tumor periphery and located around vessels in the central parts of the tumor. Colocalization of doxorubicin and hypoxic cells showed no distribution of drug into hypoxic areas. Dynamic contrastenhanced magnetic resonance imaging (MRI) 1 day before the injection of Caelyx and 2 days after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with Caelyx induces synergistic treatment effects. Improved intratumoral drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.