Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin

• Published in: Cancer research (Chicago, Ill.) Vol. 53; no. 17; pp. 3992 - 3997
• Main Author: KOCH, C. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.1993
• Subjects: Animals; Biological and medical sciences; Cell Hypoxia - drug effects; Cell Hypoxia - physiology; Cell Line; Cricetinae; Cricetulus; Fibroblasts; Medical sciences; Misonidazole - analogs & derivatives; Misonidazole - pharmacology; Oxygen; Radiation therapy and radiosensitizing agent; Radiation-Sensitizing Agents - pharmacology; Treatment with physical agents; Treatment. General aspects; Triazines - pharmacology; Tumors; Nitro compound; Cell culture; Imidazole derivatives; Cytotoxicity; Aziridine derivatives; Radiotherapy; In vitro; Chemical reduction; Resistance; Radiosensitizing agent; Animal; Metabolic activation; V79-Cell line; Hypoxia; Reversibility; Mechanism of action; Oxygen pressure
• ISSN: 0008-5472; 1538-7445

Toxicity from drugs activated by bioreductive metabolism has been suggested as a means to eliminate the treatment resistance caused by hypoxic tumor cells. In general, drugs have been selected to maximize the hypoxic cytotoxicity ratio [exposure (drug concentration x time) in air:exposure in nitrogen] to cause equal toxicity. On this basis, two recently developed drugs have very similar characteristics; an aziridine derivative of misonidazole (RSU1069) and a benzotriazine di-N-oxide (SR4233). The oxygen dependence of the toxic response has not previously been characterized. This report shows that the toxicity from SR4233 extends over a much greater range of oxygen concentrations than does that of RSU1069. Furthermore, unlike all previous drugs studied, the toxicity of SR4233 does not level off at high oxygen concentrations, but continues to decrease as the oxygen concentration increases. For 1 mM oxygen (the solubility of oxygen in medium at 37 degrees C equilibrated with 100% oxygen and water vapor) the toxicity from SR4233 is at least 2000-fold less than that for hypoxia. Modeling the effect of oxygen on combined radiation and toxicity shows that radiation plus SR4233 should be much more effective in eliminating hypoxic cells than radiation plus RSU1069. The unusual oxygen dependence of toxicity by SR4233 may indicate a unique biochemical activation process.