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Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model

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Abstract

Background

Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood–brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.

Methods

Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.

Results

After dosing of oral TMZ only, ECF-TMZ mean-C max and area under the concentration curve(AUC0–∞) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C max and AUC0–∞ were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C max and AUC0–∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB “normalization” profile following cediranib treatment.

Conclusions

In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.

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Acknowledgments

We would like to thank John Laterra, M.D., Bachchu Lal, Ph.D., Ming Zhao, Ph.D., Ping He, and Teresia Wanjiku, MHS, for their technical support. This work was supported by the American Physicians Fellowship (APF) for Medicine in Israel (Rachel Grossman), the American Cancer Society Research Scholar Grant (RSG-08-119-01-CCE), and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005) and the Shared Instrument Grant (1S10RR026824-01).The work was also supported by the generosity of Peter and Ali Jennison. The project described was supported by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine Baltimore, 1550 Orleans Street/Cancer Research Building II Room 2M45, Baltimore, MD, 21231, USA

    Rachel Grossman, Betty Tyler, Patti Zadnik, Ursalan Khan & Henry Brem

  2. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michelle A. Rudek

  3. Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Eugene Kim & Henry Brem

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jaishri O. Blakeley

  5. Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Arvind P. Pathak

  6. Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Arvind P. Pathak & Henry Brem

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  1. Rachel Grossman
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Correspondence to Betty Tyler.

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Grossman, R., Tyler, B., Rudek, M.A. et al. Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. Cancer Chemother Pharmacol 72, 93–100 (2013). https://doi.org/10.1007/s00280-013-2172-3

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  • DOI: https://doi.org/10.1007/s00280-013-2172-3

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