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Recurrent Low-Dose Chemotherapy to Inhibit and Oxygenate Head and Neck Tumors

  • Nadeem Khan
  • Huagang Hou
  • Sassan Hodge
  • Muthulakshmi Kuppusamy
  • Eunice Y. Chen
  • Alan Eastman
  • Periannan Kuppusamy
  • Harold M. Swartz
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 812)

Abstract

A lack of strategy to counteract hypoxia (pO2 < 10–15 mmHg) and technique to repeatedly measure tumor pO2 has restricted therapeutic optimization. We report the results obtained with an innovative anti-angiogenic strategy of recurrent low-dose (metronomic) chemotherapy to modulate hypoxia and growth of the Head and Neck tumor xenografts.

The FaDu tumors were established in the flank of immune deficient mice and EPR oximetry with lithium phthalocyanine crystals was used to follow the temporal changes in tumor pO2 on treatment with gemcitabine including controls for three weeks. The FaDu tumors were hypoxic with a baseline (pre-treatment) pO2 of 2–8 mmHg. A transient increase in the tumor pO2 was evident on day 3 on treatment with a conventional schedule of gemcitabine (150 mg/kg, d1, d8, d15). No significant change in the tumor pO2 on treatment with metronomic gemcitabine (25 mg/kg on d1, d3, d5 for 3 weeks) was observed. However, tumor pO2 increased significantly on d15–d18 during treatment with a metronomic schedule of 15 mg/kg gemcitabine (d1, d3, d5 for 3 weeks). A modest decrease in the tumor growth was evident on treatment with conventional gemcitabine. Notably, tumor growth was significantly inhibited by metronomic (25 and 15 mg/kg) gemcitabine treatment. The immunohistochemistry (IHC) analyses of the tumor samples indicate a decrease in HIF-1α and TSP-1 on treatment with metronomic gemcitabine.

In conclusion, a significant inhibition of tumor growth on treatment with metronomic gemcitabine was observed; however, the increase in pO2 was dose dependent. EPR oximetry can be used to follow the temporal changes in tumor pO2 to identify a therapeutic window on treatment with metronomic chemotherapy for potential combination with radiotherapy.

Keywords

Chemotherapy Anti-angiogenesis Vascular normalization Head and neck cancer Partial pressure of oxygen (pO2Electron paramagnetic resonance (EPR) oximetry Hypoxia inducible factor (HIF) Thrombospondin (TSP) 

Notes

Acknowledgments

Pilot Program Project funded by the Norris Cotton Cancer Center, Department of Radiology, and the EPR Center, Geisel School of Medicine, Hanover, NH.

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Copyright information

© Springer Science+Business Media, LLC 2014

Authors and Affiliations

  • Nadeem Khan
    • 1
    • 2
  • Huagang Hou
    • 1
    • 2
  • Sassan Hodge
    • 3
  • Muthulakshmi Kuppusamy
    • 1
    • 2
  • Eunice Y. Chen
    • 3
  • Alan Eastman
    • 4
  • Periannan Kuppusamy
    • 1
    • 2
  • Harold M. Swartz
    • 5
  1. 1.EPR Center for Viable Systems, Department of RadiologyThe Geisel School of MedicineHanoverUSA
  2. 2.Norris Cotton Cancer CenterLebanonUSA
  3. 3.Department of SurgeryDartmouth-Hitchcock Medical Center, One Medical Center DriveLebanonUSA
  4. 4.Department of Pharmacology and ToxicologyThe Geisel School of MedicineHanoverUSA
  5. 5.EPR Center for the Study of Viable SystemsThe Geisel School of Medicine at DartmouthLebanonUSA

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