Antiangiogenic effects of noscapine enhance radioresponse for GL261 tumors.
OBJECTIVE
To assess the effects of noscapine, a tubulin-binding drug, in combination with radiation in a murine glioma model.


METHODS
The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation, or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation, tumors were resected and immunostained to measure proliferation rate, apoptosis, and angiogenic activity.


RESULTS
Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, and 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, and a decrease in tumor vessel density compared with tumors treated with radiation alone.


CONCLUSIONS
Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation, resulting in a significant tumor growth delay. An antiangiogenic mechanism contributed to the effect. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug.
Newcomb
Elizabeth W
EW
Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. newcoe01@med.nyu.edu
Lukyanov
Yevgeniy
Y
Alonso-Basanta
Michelle
M
Esencay
Mine
M
Smirnova
Iva
I
Schnee
Tona
T
Shao
Yongzhao
Y
Devitt
Mary Louise
ML
Zagzag
David
D
McBride
William
W
Formenti
Silvia C
SC
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009665:Noscapine / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D020533:Angiogenesis Inhibitors; D009665:Noscapine; D001973:Bromodeoxyuridine