title: Recurrent low-dose chemotherapy to inhibit and oxygenate head and neck tumors.
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.
authors.affiliation: EPR Center for Viable Systems, Department of Radiology, The Geisel School of Medicine, Hanover, NH, 03755, USA. Nadeem.Khan@Dartmouth.Edu.|Norris Cotton Cancer Center, Lebanon, NH, 03756, USA. Nadeem.Khan@Dartmouth.Edu.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Khan
authors.affiliation: EPR Center for Viable Systems, Department of Radiology, The Geisel School of Medicine, Hanover, NH, 03755, USA.|Norris Cotton Cancer Center, Lebanon, NH, 03756, USA.
authors.forename: Huagang
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Sassan
authors.initials: S
authors.lastname: Hodge
authors.affiliation: EPR Center for Viable Systems, Department of Radiology, The Geisel School of Medicine, Hanover, NH, 03755, USA.|Norris Cotton Cancer Center, Lebanon, NH, 03756, USA.
authors.forename: Muthulakshmi
authors.initials: M
authors.lastname: Kuppusamy
authors.affiliation: Department of Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, The Geisel School of Medicine, Hanover, NH, 03755, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
authors.affiliation: EPR Center for Viable Systems, Department of Radiology, The Geisel School of Medicine, Hanover, NH, 03755, USA.|Norris Cotton Cancer Center, Lebanon, NH, 03756, USA.
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: EPR Center for the Study of Viable Systems, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Harold M
authors.initials: HM
authors.lastname: Swartz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010100:Oxygen / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D010100:Oxygen; D000093542:Gemcitabine
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