Antitumor efficacy improved by local delivery of species-specific endostatin.
OBJECTIVE
Conflicting results have been reported concerning the antitumor efficacy of the angiogenesis inhibitor endostatin. This may be due to differences in the biological distribution of endostatin between studies or to the varying biological efficacies of the different protein forms that were examined. To address this issue, the authors used a local delivery approach in which each tumor cell secreted endostatin, providing uniform endostatin levels throughout the tumors. This allowed a direct assessment of the biological efficacy of soluble endostatin in vivo.


METHODS
The authors genetically engineered BT4C gliosarcoma cells so that they would stably express and secrete either the human or murine form of endostatin. Endostatin-producing cells or mock-infected cells were implanted intracerebrally in syngeneic BD-IX rats. The antitumor efficacy of endostatin was evaluated on the basis of survival data and tumor volume comparisons. In addition, microvascular parameters were assessed. The authors confirmed the continuous release of endostatin by the BT4C cells. A magnetic resonance imaging-assisted comparison of tumor volumes revealed that local production of murine endostatin significantly inhibited tumor growth. Notably, 40% of the animals in this treatment group experienced long-term survival without histologically verifiable tumors 7 months after cell implantation. After local treatment with murine endostatin, tumor blood plasma volumes were reduced by 71%, microvessel density counts by 84%, and vascular area fractions by 75%. In contrast, human endostatin did not inhibit tumor growth significantly in this model. Centrally located regions of necrosis were present in tumors secreting both the human and the murine species-specific form of endostatin.


CONCLUSIONS
The results suggest that endostatin inhibits tumor angiogenesis in vivo in a species-specific manner.
Huszthy
Peter C
PC
Gene Therapy Program, Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway. Peter.Hsuzthy@helse-bergen.no
Brekken
Christian
C
Pedersen
Tina B
TB
Thorsen
Frits
F
Sakariassen
Per Oystein
PO
Skaftnesmo
Kai Ove
KO
Haraldseth
Olav
O
Lønning
Per Eystein
PE
Bjerkvig
Rolf
R
Enger
Per Oyvind
PO
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D017690:Cell Transplantation; D043169:Endostatins / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D005818:Genetic Engineering; D018316:Gliosarcoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D051381:Rats; D013534:Survival; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D043169:Endostatins