The objective of this application is to develop new, unique therapies to more completely and rapidly control bulk cancer within the liver. One element of the applicant's approach is the use of hepatic arterial administration of Yttrium 90 glass microspheres (Y90 MS) to selectively irradiate hypervascular regions of tumors. His current phase I clinical study has found no dose-related toxicity at 12,500 rads of Y90 MS. This investigation will be continued to define the maximum tolerated dose (anticipated from his animal studies at greater than or equal to 20,000 rads). Based upon his studies demonstrating improvement in tumor to normal liver deposition of tracer microspheres with short HA infusion of epinephrine, a phase I-II study utilizing epinephrine with Y90 MS subsequently will be developed using a balloon occlusion catheter to prevent extrahepatic reflux of Y90 MS. The second element of the applicant's approach is the addition of HA 5-bromo-2'-deoxyuridine (BUDR) as a radiosensitizer, a treatment that is pharmacologically rational as substantiated by his animal and clinical studies. In vivo antitumor effects resulting from BUDR-induced radiosensitization with Y9O MS will be explored in rabbits hearing the VX2 tumor (intrahepatically implanted). Toxicology studies will be performed in dogs at relevant dose/schedules of HA BUDR and Y90 MS (as was previously done for Y90 MS alone). The results of the clinical studies of Y90 MS alone and of the animal studies combining Y90 MS with BUDR will be utilized during the 04-05 grant years to develop a phase I study of the combination and to gain approval of same from the NCI and FDA.
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