Hypoxia-specific drug tirapazamine does not abrogate hypoxic tumor cells in combination therapy with irinotecan and methylselenocysteine in well-differentiated human head and neck squamous cell carcinoma An253 xenografts

Well-differentiated hypoxic regions in head and neck squamous cell carcinoma like in A253 xenografts are avascular and, therefore, hinder drug delivery leading to drug resistance and tumor regrowth. Methylselenocysteine ( MSC, 0.2 mg/mouse per day per oral for 35 days starting 7 days before the first irinotecan (CPT-11)) has been found to increase efficacy of a wide variety of chemotherapeutic agents including CPT-11 ( 100 mg/kg per week x 4 intravenously). Whereas CPT-11 leads to a 10% complete response (CR) in A253 xenografts, the combination of MSC and CPT-11 increased the CR to 70%. Surviving tumors were found to consist largely of avascular hypoxic regions. Here, we investigated the combination of tirapazamine (TPZ, 70 mg/kg per week intraperitoneal x 4 administered 3 or 72 hours before CPT-11), a bioreductive drug in clinical trial with selective toxicity for hypoxic cells, with MSC and CPT-11 in further enhancing the cure rates. Tumor response, change in tumor hypoxic regions, and DNA damage were monitored in vivo. Tirapazamine administered 3 hours before CPT-11 in combination with MSC + CPT-11 led to a lower tumor burden. Tirapazamine did not increase cure rate beyond that of MSC + CPT-11 combination and was instead found to decrease cures with no evidence of an increased DNA damage or a significant reduction in avascular hypoxic tumor regions. CD31 immunostaining in A253 demonstrated disruption of tumor vessels by TPZ that could lower cytotoxic drug delivery to carbonic anhydrase IX-positive hypoxic tumor cells and may explain at least partially these unexpected results.