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

A lack of strategy to counteract hypoxia (pO(2)<10-15 mmHg) and technique to repeatedly measure tumor pO(2) 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 pO(2) on treatment with gemcitabine including controls for three weeks. The FaDu tumors were hypoxic with a baseline (pre-treatment) pO(2) of 2-8 mmHg. A transient increase in the tumor pO(2) 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 pO(2) on treatment with metronomic gemcitabine (25 mg/kg on d1, d3, d5 for 3 weeks) was observed. However, tumor pO(2) 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-1 alpha 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 pO(2) was dose dependent. EPR oximetry can be used to follow the temporal changes in tumor pO(2) to identify a therapeutic window on treatment with metronomic chemotherapy for potential combination with radiotherapy.