Radiosensitization of a mouse tumor model by sustained intra-tumoral release of etanidazole and tirapazamine using a biodegradable polymer implant device.
OBJECTIVE
Drug toxicities are 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, intra-tumoral drug concentrations could be achieved without the cumulative toxicity associated with repeated systemic drug dosage. In this paper we describe the use of a biodegradable polymer implant for sustained intra-tumoral release of high concentrations of drugs targeting hypoxic cells.


METHODS
The RIF-1 tumor was implanted subcutaneously or intramuscularly in C3H mice and irradiated with 60Co gamma rays. The drug delivery device was the co-polymer CPP-SA;20:80 into which the drug was homogeneously incorporated. The hypoxic radiosensitizer Etanidazole or the bioreductive drug Tirapazamine were delivered intra-tumorally by means of implanted polymer rods containing the drugs. Tumor growth delay (TGD) was used as the 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 was effective in sub-cutaneous tumors. Since both drugs target hypoxic cells we hypothesized that the lack of effect in the subcutaneous tumor was attributable to the smaller size of the hypoxic fraction in this tumor model. This 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 Tirapazamine and that, in conjunction with radiation, this approach could improve treatment outcome in tumors which contain a sub-population of hypoxic, radioresistant cells.
Yapp
D T
DT
Department of Radiation Oncology, McGill University, Montréal, Quebec, Canada.
Lloyd
D K
DK
Zhu
J
J
Lehnert
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015687:Cell Hypoxia; D004343:Drug Implants; D017341:Etanidazole / Q000008:administration & dosage*; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D011108:Polymers; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011879:Radiotherapy Dosage; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D004343:Drug Implants; D011108:Polymers; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D017341:Etanidazole