Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma

Phyllis R. Wachsberger, Randy M Burd, Nichol Marero, Constantine Daskalakis, Anderson Ryan, Peter McCue, Adam P. Dicker

Research output: Contribution to journalArticle

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Abstract

Purpose: 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-NG-nitro-arginine 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 diameter2 × 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.

Original languageEnglish (US)
Pages (from-to)835-842
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number2 I
StatePublished - Jan 15 2005
Externally publishedYes

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Glioblastoma
Blood Vessels
Neoplasms
Radiation
NG-Nitroarginine Methyl Ester
Growth
Heterografts
Nude Mice
Nitric Oxide Synthase
N-acetylcochinol-O-phosphate
Necrosis
Oxygen
L Forms
Ionizing Radiation
Tumor Burden
England
Radiotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wachsberger, P. R., Burd, R. M., Marero, N., Daskalakis, C., Ryan, A., McCue, P., & Dicker, A. P. (2005). Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma. Clinical Cancer Research, 11(2 I), 835-842.

Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma. / Wachsberger, Phyllis R.; Burd, Randy M; Marero, Nichol; Daskalakis, Constantine; Ryan, Anderson; McCue, Peter; Dicker, Adam P.

In: Clinical Cancer Research, Vol. 11, No. 2 I, 15.01.2005, p. 835-842.

Research output: Contribution to journalArticle

Wachsberger, PR, Burd, RM, Marero, N, Daskalakis, C, Ryan, A, McCue, P & Dicker, AP 2005, 'Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma', Clinical Cancer Research, vol. 11, no. 2 I, pp. 835-842.
Wachsberger PR, Burd RM, Marero N, Daskalakis C, Ryan A, McCue P et al. Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma. Clinical Cancer Research. 2005 Jan 15;11(2 I):835-842.
Wachsberger, Phyllis R. ; Burd, Randy M ; Marero, Nichol ; Daskalakis, Constantine ; Ryan, Anderson ; McCue, Peter ; Dicker, Adam P. / Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 2 I. pp. 835-842.
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abstract = "Purpose: 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-NG-nitro-arginine 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 diameter2 × 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.",
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N2 - Purpose: 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-NG-nitro-arginine 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 diameter2 × 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.

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