Tumor pO2 as a Surrogate Marker to Identify Therapeutic Window during Metronomic Chemotherapy of 9L Gliomas

  • Sriram Mupparaju
  • Huagang Hou
  • Jean P. Lariviere
  • Harold M. Swartz
  • Nadeem Khan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 701)

Abstract

Glioblastomas are aggressive and highly vascularized primary brain tumors with a 5-year survival rate of less than 10%. Approaches targeting tumor vasculature are currently being investigated to achieve therapeutic benefits for this fatal malignancy. However, lack of suitable markers that can be used to monitor therapeutic effects during such treatments has restricted their optimization. We have focused on the development of tumor pO2 as a surrogate marker to identify the therapeutic window during metronomic chemotherapy.We report the effect of four weekly administrations of cyclophosphamide (140 mg/Kg, i.p), a chemo drug, on tumor pO2 and growth of subcutaneous 9L tumors in SCID mice. The repeated measurement of tumor pO2 was carried out using in vivo EPR oximetry. The subcutaneous 9L tumors were hypoxic with a pre-treatment tumor pO2 of 5.1 ± 1 mmHg and a tumor volume of 236 ± 45 mm3 on day 0. The tumor pO2 increased significantly to 26.2 ± 2 mmHg on day 10, and remained at an elevated level till day 31 during weekly treatments with cyclophosphamide. The tumor pO2 then declined to 20 ± 9 mmHg on day 43. The tumor volume of the control group increased significantly with no change in tumor pO2over days.Results indicate a transient increase in tumor pO2 duringmetronomic chemotherapy of 9L gliomas and could be potentially used as amarker to identify vessel normalization during metronomic chemotherapy. The ability to identify therapeutic window non-invasively using EPR oximetry can have a significant impact on the optimization of clinical protocols. In vivo EPR oximetry is currently being tested for repeated pO2 measurements in patients with superficial tumors.

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References

  1. 1.
    Buckner JC. Factors influencing survival in high-grade gliomas. Semin Oncol 30:10-14, 2003.PubMedCrossRefGoogle Scholar
  2. 2.
    Buckner JC, Brown PD, O’Neill BP,Meyer FB,Wetmore CJ, Uhm JH. (2007) Central nervous system tumors. Mayo Clin Proc 82:1271-1286.PubMedCrossRefGoogle Scholar
  3. 3.
    DeAngelis LM. (2001) Brain tumors. N Engl J Med 344:114-123.PubMedCrossRefGoogle Scholar
  4. 4.
    Fukumura D, Jain RK. (2007)Tumor microvasculature and microenvironment: targets for antiangiogenesis and normalization. Microvasc Res 74:72-84.PubMedCrossRefGoogle Scholar
  5. 5.
    Hou H, Khan N, Grinberg OY, Yu H, Grinberg SA, Lu S, Demidenko E, Steffen RP, Swartz HM. (2007)The effects of Efaproxyn (efaproxiral) on subcutaneous RIF-1 tumor oxygenation and enhancement of radiotherapy-mediated inhibition of tumor growth in mice. Radiat Res 168:218-225.PubMedCrossRefGoogle Scholar
  6. 6.
    Hou H, Lariviere JP, Demidenko E, Gladstone D, Swartz H, Khan N. (2009) Repeated tumor pO(2) measurements by multi-site EPR oximetry as a prognostic marker for enhanced therapeutic efficacy of fractionated radiotherapy. Radiother Oncol 91:126-131.PubMedCrossRefGoogle Scholar
  7. 7.
    Jain RK. (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58-62.PubMedCrossRefGoogle Scholar
  8. 8.
    Khan N, Williams B, Swartz H. (2006) Clinical applications of in vivo EPR: rationale and initial results. Applied Magn Reson 30:185-199,.CrossRefGoogle Scholar
  9. 9.
    Khan N,Williams BB, Hou H, Li H, Swartz HM. (2007)Repetitive tissue pO2 measurements by electron paramagnetic resonance oximetry: current status and future potential for experimental and clinical studies. Antioxid Redox Signal 9:1169-1182.PubMedCrossRefGoogle Scholar
  10. 10.
    Kim JT, Kim JS, Ko KW, Kong DS, Kang CM, Kim MH, Son MJ, Song HS, Shin HJ, Lee DS, Eoh W, Nam DH. (2006) Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol Rep 16:33-39.PubMedGoogle Scholar
  11. 11.
    Ma J,Waxman DJ (2007).Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment. Mol Cancer Ther 6:2879-2890.PubMedCrossRefGoogle Scholar
  12. 12.
    Swartz HM, Clarkson RB. (1998) The measurement of oxygen in vivo using EPR techniques. Phys Med Biol 43:1957-1975.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhou Q, Guo P, Wang X, Nuthalapati S, Gallo JM. (2007) Preclinical pharmacokinetic and pharmacodynamic evaluation ofmetronomic and conventional temozolomide dosing regimens. J Pharmacol Exp Ther 321:265-275.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Sriram Mupparaju
    • 1
    • 2
  • Huagang Hou
    • 1
    • 2
  • Jean P. Lariviere
    • 1
  • Harold M. Swartz
    • 1
  • Nadeem Khan
    • 1
    • 2
  1. 1.EPR Center for Viable SystemsDartmouth Medical SchoolHanoverUSA
  2. 2.Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical CenterLebanonUSA

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