Combined chemotherapy of murine mammary tumors by local activation of the prodrugs ifosfamide and 5-fluorocytosine

The success of chemotherapeutic intervention is limited because the necessa ry high local drug doses cannot be achieved without systemic toxicity. Appl ication of suicide genes (SGs) and direct conversion of prodrugs (PDs) to t oxic metabolites in situ by SGs may enhance the efficacy of chemotherapy. T o evaluate this strategy in two murine breast cancer models, TS/A and GR, w e injected cellulose sulfate capsules harboring cat kidney cells expressing the SGs cytosine deaminase and cytochrome P450 2B1 (CYP2B1) intratumorally . The PDs 5-fluorocytosine and ifosfamide were administered in 3-day interv als. The effect of in situ chemotherapy with each PD alone and the combinat ion was analyzed over a period of 100 days. The results reveal that for TS/ A tumors, the antitumoral effect mediated by CYP2B1 is more efficient than that of cytosine deaminase, whereas for GR tumors, both systems worked equa lly well. Furthermore, we find additive toxicity using both SG/PD systems f or both TS/A and GR tumors.