RSR13: Effects on tumor oxygenation and response to therapy

Abstract

RSR13,[2,4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid], is a new allosteric effector of hemoglobin which causes hemoglobin to off-load oxygen more readily. Intravenous administration of RSR13 to rats bearing the 13762 mammary carcinoma resulted in a decrease in the hypoxic fraction (percent of pO2 readings <5 mmHg) of the tumor that was dependent upon RSR13 dose and was maximal at 30 min after RSR13 administration. Breathing carbogen (95% oxygen/5% carbon dioxide) along with RSR13 administration markedly increased tumor oxygenation. Intravenous infusion of RSR13 (200 mg/kg) over 60 min resulted in maximal tumor oxygenation at 40 min into the infusion. By 30 min after completion of the infusion, tumor oxygenation had returned to baseline. RSR13 was very modestly cytotoxic to EMT-6 murine mammary carcinoma cells when administered to tumor-bearing animals in doses up to 500 mg/kg and was not toxic toward the bone marrow colony forming unit-granulocyte-macrophage (CFU-GM) from the same animals. Administration of RSR13 to animals bearing the Lewis lung carcinoma prior to each fraction of a fractionated radiation therapy regimen resulted in dose modification with dose-modifying factors up to 1.66. RSR13 administration also resulted in decreased numbers of lung metastases in these same animals. When RSR13 was administered on days 4–18, the modification of fractionated radiation remained the same but the number of lung metastases was decreased further. The combination of RSR13 with chemotherapy (cyclophosphamide, adriamycin, 5-fluorouracil, or cis-diamminedichloroplatinum II) resulted in 1.2–1.5-fold increases in the response of the primary tumor and marked decreases in lung metastases. In animals bearing the MB-49 bladder carcinoma, administration of RSR13 resulted in increased responses to both fractionated radiation therapy and chemotherapy and marked decreases in lung metastases. RSR13 was effective in decreasing the number of lung colonies formed by intravenously injected tumor cells if administered on the day prior to, on the same day as, or on the day after the tumor cells. Further investigation of this interesting new drug is warranted. © 1996 Wiley-Liss, Inc.