Radiosensitization of a mouse tumor model by sustained intra-tumoral release of Etanidazole and Tirapazamine using a biodegradable polymer implant device

Background and purpose: Drug toxicities ale often a limiting factor in long term treatment regimes used in conjunction with radiotherapy. If the drug could be localized to the tumor site and released slowly, then optimal, int ra-tumoral drug concentrations could be achieved without the cumulative tox icity associated with repeated systemic drug dosage. In this paper we descr ibe the use of a biodegradable polymer implant for sustained intra-tumoral release of high concentrations of drugs targeting hypoxic cells. Materials and methods: The RIF-1 tumor was implanted subcutaneously or intr amuscularly in C3H mice and irradiated with Co-60 gamma rays. The drug deli very device was the co-polymer CPP-SA;20:80 into which the drug was homogen eously incorporated. The hypoxic radiosensitizer Etanidazole or the bioredu ctive drug Tirapazamine were delivered intra-tumorally by means of implante d polymer rods containing the drugs. Tumor growth delay (TGD) was used as t he end point in these experiments. Results: Both Etanidazole and Tirapazamine potentiated the effects of acute and fractionated radiation in the intra-muscular tumors but neither drug w as effective in sub-cutaneous tumors. Since both drugs target hypoxic cells we hypothesized that the lack of effect in the subcutaneous tumor was attr ibutable to the smaller size of the hypoxic fraction in this tumor model. T his was confirmed using the hypoxia marker EF5. Conclusions: These results indicate that the biodegradable polymer implant is an effective vehicle for the intra-tumoral delivery of Etanidazole and T irapazamine and that, in conjunction with radiation, this approach could im prove treatment outcome in tumors which contain a sub-population of hypoxic , radioresistant cells. (C) 1999 Elsevier Science Ireland Ltd. All rights r eserved.