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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Ensminger, W D; Walker, S C; Stetson, P L et al. (1994) Clinical pharmacology of hepatic arterial infusions of 5-bromo-2'-deoxyuridine. Cancer Res 54:2121-4
Andrews, J C; Walker, S C; Ackermann, R J et al. (1994) Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up. J Nucl Med 35:1637-44
Marn, C S; Andrews, J C; Francis, I R et al. (1993) Hepatic parenchymal changes after intraarterial Y-90 therapy: CT findings. Radiology 187:125-8
Stetson, P L; Domino, E F; Sneyd, J R (1993) Determination of plasma propofol levels using gas chromatography-mass spectrometry with selected-ion monitoring. J Chromatogr 620:260-7
Roberson, P L; Ten Haken, R K; McShan, D L et al. (1992) Three-dimensional tumor dosimetry for hepatic yttrium-90-microsphere therapy. J Nucl Med 33:735-8
Stetson, P L; Shukla, U A; Ensminger, W D (1989) Stability of trimetrexate, a new non-classical antifolate, in infusion solutions. J Chromatogr 464:163-71
Knol, J A; Stetson, P L; Wagner, J G et al. (1989) 5-Bromo-2'-deoxyuridine incorporation into DNA in hepatic VX2 tumor-bearing rabbits. J Surg Res 47:112-6
Andrews, J C; Knol, J; Wollner, I et al. (1989) Floxuridine-associated sclerosing cholangitis. A dog model. Invest Radiol 24:47-51
Wagner, J G; Stetson, P L; Knol, J A et al. (1989) Steady-state arterial and hepatic venous plasma concentrations of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine in animals--drugs which are subject to both splanchnic and extra-splanchnic elimination. Sel Cancer Ther 5:193-203
Andrews, J C; Walker-Andrews, S C; Juni, J E et al. (1989) Modulation of liver tumor blood flow with hepatic arterial epinephrine: a SPECT study. Radiology 173:645-7

Showing the most recent 10 out of 22 publications