tirapazamine and Pharyngeal-Neoplasms

Tirapazamine (TPZ), a bioreductive drug with selective toxicity for hypoxic cells in tumors, is currently in Phase III clinical trials. It has been suggested to have a dual mechanism of action, both generating DNA radicals and oxidizing these radicals to form DNA breaks; whether the second (radical oxidation) step is rate-limiting in cells is not known. In this study we exploit the DNA radical oxidizing ability of the 1-N-oxide metabolite of TPZ, SR 4317, to address this question. SR 4317 at high, but nontoxic, concentrations potentiated the hypoxic (but not aerobic) cytotoxicity of TPZ in all four of the human tumor cell lines tested (HT29, SiHa, FaDu, and A549), thus providing a 2-3-fold increase in the hypoxic cytotoxicity ratio. In potentiating TPZ, SR 4317 was 20-fold more potent than the hypoxic cell radiosensitizers misonidazole and metronidazole but was less potent than misonidazole as a radiosensitizer, suggesting that the initial DNA radicals from TPZ and radiation are different. SR 4317 had favorable pharmacokinetic properties in CD-1 nude mice; coadministration with TPZ provided a large increase in the SR 4317 plasma concentrations relative to that for endogenous SR 4317 from TPZ. It also showed excellent extravascular transport properties in oxic and anoxic HT29 multicellular layers (diffusion coefficient 3 x 10(-6) cm(2)s(-1), with no metabolic consumption). Coadministration of SR 4317 (1 mmol/kg) with TPZ at a subtherapeutic dose (0.133 mmol/kg) significantly enhanced hypoxic cell killing in HT29 tumor xenografts without causing oxic cell killing, and the combination at its maximum tolerated dose was less toxic to hypoxic cells in the retina than was TPZ alone at its maximum tolerated dose. This study demonstrates that benzotriazine mono-N-oxides have potential use for improving the therapeutic utility of TPZ as a hypoxic cytotoxin in cancer treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Drug Synergism; Female; Humans; Lung Neoplasms; Mice; Pharyngeal Neoplasms; Tirapazamine; Triazines; Uterine Cervical Neoplasms

The goal of this study was to compare, with a human tumor xenograft, two different strategies for increasing tumor response to fractionated irradiation, namely, oxygenating the hypoxic tumor cells with carbogen and nicotinamide, or killing these cells with the hypoxic cytotoxin, tirapazamine (TPZ). We used the human hypopharyngeal squamous cell carcinoma cell line FaDu implanted in immune-deficient SCID mice and assessed its response to radiation by cell survival and by growth delay. The tumors were irradiated either once or twice daily with 2 or 2.5 Gy/fraction with either TPZ (0.08 mmol/kg) or nicotinamide (1,000 mg/kg) with carbogen breathing. We also tested the effect of giving TPZ on alternate days, or daily during the first half of the course, the second half, or for the whole course of radiation. We found that adding TPZ or nicotinamide with carbogen to the fractionated radiation regimen enhanced the response of the human xenograft. The enhancement was somewhat greater (though not significantly so) for TPZ, especially when given with each radiation dose. In conclusion, adding TPZ, or nicotinamide plus carbogen, to fractionated irradiation enhanced the response of this human tumor xenograft to fractionated irradiation. Consistent with theoretical modeling, there was a greater enhancement of the radiation response of the tumor when TPZ was given with each radiation dose than when given with only half of the radiation doses.

Topics: Animals; Carbon Dioxide; Carcinoma, Squamous Cell; Cell Survival; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease Models, Animal; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Female; Humans; Male; Mice; Mice, SCID; Neoplasm Transplantation; Niacinamide; Oxygen; Oxygen Consumption; Pharyngeal Neoplasms; Radiation Dosage; Radiation-Sensitizing Agents; Sensitivity and Specificity; Tirapazamine; Triazines; Tumor Cells, Cultured