Interaction of the bioreductive drug sr 4233 and photodynamic therapy using photofrin in a mouse tumor model

Abstract

Purpose : Combining the bioreductive drug SR 4233 with interstitial photodynamic therapy to improve efficacy. Methods and Materials : RIFT tumors were implanted subcutaneously in mice and treated with interstitial photodynamic therapy. The bioreductive drug SR 4233 (a benzotriazine which exhibits preferential cell killing under hypoxic conditions) was combined with photodynamic therapy to exploit the induced hypoxia. SR 4233 was given to mice prior to or just after illumination. The effect of multiple SR 4233 injections given over the first 3 days after treatment was also evaluated. Results : The results from experiments with a 24 hr interval between Photofrin and illumination showed that SR 4233 produced only a small additional growth delay compared with photodynamic therapy alone (light doses of 300 or 400 J/cm, combined with 6 X 15 mg/kg SR 4233). Some cures (6/60), however, were found in groups treated with 200 to 400 J/cm with SR 4233, whereas only two cures (2/77) occurred at light doses up to 400 J/ cm after photodynamic therapy alone. Reducing the interval between Photofrin injection and illumination increased the number of cures in the combination group, although this was associated with a marked increase in toxicity. A small increase in cure rate was observed for the combination of photodynamic therapy (6 hr interval) and SR 4233, although this was not significant due to the limited number of mice that survived treatment. Conclusion : Only a limited effect of combining SR 4233 and interstitial photodynamic therapy was observed in this tumor model. A possible explanation could be the rapid conversion of SR 4233 into inactive metabolites.