Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma.
OBJECTIVE
The effect of ZD6126 on tumor oxygen tension and tumor growth delay in combination with ionizing radiation was examined in the human U87 glioblastoma tumor model. Resistance to ZD6126 treatment was investigated with the nitric oxide synthase inhibitor, l-N(G)-nitroarginine methyl ester (hydrochloride; l-NAME/active form, l-NNA).


METHODS
U87 human xenografts were grown in athymic nude mice. ZD6126 was given with or without l-NNA. Tumor oxygen tension was measured using the Oxford Oxylite (Oxford, England) fiberoptic probe system. Tumor volume was determined by direct measurement with calipers and calculated by the formula [(smallest diameter(2) x widest diameter)/2].


RESULTS
Multiple doses of ZD6126 treatment (three doses) had a significant effect on tumor growth delay, reducing the average daily tumor growth rate from 29% to 16%. When given 1 hour before radiation, ZD6126 caused an acute increase in hypoxia in U87 tumors, and reduced tumor growth delay compared with that of radiation alone. The combination of ZD6126 given after radiation, either as a single dose or in multiple doses, had greater or similar antitumor activity compared with radiation alone. Twenty-four hours after administration, a single dose of ZD6126 induced little (10 +/- 8%) necrosis in U87 xenografts. l-NNA, when given in combination with ZD6126, significantly enhanced the effectiveness of ZD6126 in inducing tumor necrosis.


CONCLUSIONS
Our observation that ZD6126-induced tumor hypoxia can decrease radiation response when ZD6126 is given prior to radiation indicates the importance of scheduling. Our findings suggest that the optimal therapeutic benefit of ZD6126 plus radiation in human glioblastoma may require multiple dosing in combination with a nitric oxide synthase inhibitor, to be scheduled following radiotherapy.
Wachsberger
Phyllis R
PR
Department of Radiation Oncology, Division of Clinical Pharmacology, Bodine Center for Cancer Treatment, Thomas Jefferson University Hospital, 111 South 11th Street, Philadelphia, PA 19107, USA. Phyllis.wachsberger@mail.tju.edu
Burd
Randy
R
Marero
Nichol
N
Daskalakis
Constantine
C
Ryan
Anderson
A
McCue
Peter
P
Dicker
Adam P
AP
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000628:therapy; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000098:blood supply* / Q000628:therapy*; D006801:Humans; D000860:Hypoxia; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000628:therapy*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen