Preclinical Evaluation of 5-Iodo-2-pyrimidinone-2’-.deoxyribose as a Prodrug for 5-Iodo-2’-deoxyuridine-mediated Radiosensitization in Mouse and Human Tissues1

نویسندگان

  • Timothy J. Kinsella
  • Keith A. Kunugi
  • Kathleen A. Vielhuber
  • David M. Potter
  • Michael E. Fitzsimmons
  • Jerry M. Collins
چکیده

We reported previously that p.o. administered 5-iodo2-pyrimidinone-2’-deoxyribose (IPdR) was efficiently converted to 5-iodo.2’-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et aL, Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at the maximum tolerable dose. We also evaluate IPdR metabolism in cytosobic extracts from normal human liver, normal human intestine, and human colorectal cancer specimens. Athymic mice tolerated a daily p.o. bolus of up to 2 g/kg IPdR for 6 days with minimal host toxicity ( 1O% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 iM at 10 mm following a p.o. IPdR bolus of 250-1500 mg/kg. The percentage IUdR-DNA in the HT29 s.c. human tumor xenografts increased 1.5 times (2.3-3.6%) with IPdR doses above 1 g/kg/day for 6 days, whereas the percentage IUdR-DNA incorporation in two proliferating normal tissues (4-4.5% in intestine; 1.6-2.2% in bone marrow) and a quiescent normal tissue ( 1 % in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 glkglday for 6 days. In contrast, using a continuous infusion of IUdR at 100 mg/kg/day, significant systemic toxicity (>20% body weight loss) was found by day 6 of the infusion. Steady-state plasma Received 12/20/96; revised 8/24/97; accepted 9/23/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with I 8 U.S.C. Section 1734 solely to indicate this fact. I This study was supported in part by NIH Grant CA50595 (to T. J. K.). the John Veatch Memorial Fund, and Sparta Pharmaceuticals, Inc. (Research Triangle Park, NC). 2 To whom requests for reprints should be addressed. at Department of Radiation Oncology, University Hospitals of Cleveland, I 1300 Euclid Avenue, Cleveland, OH 44106-5056. Phone: (216) 844-3100; Fax: (216) 844-1038. IUdR levels were 1.0-1.2 .tM during the 6-day infusion, and percentage IUdR-DNA incorporations of 2.3, 8, 6, and 1% were measured in s.c. tumors, normal intestine, normal bone marrow, and normal liver, respectively, following the 6-day infusion. Thus, the p.o. IPdR schedule has an improved therapeutic index, based on percentage IUdR-DNA incorporation in normal and tumor tissues, compared to continuous infusion IUdR at the maximum tolerable dose in athymic mice with this human tumor xenograft. Additionally, a tumor regrowth assay to assess the radiation response of HT29 s.c. xenografts showed a 1.5-fold enhancement (time to regrow to 300% initial tumor volume) with IPdR (1000 mg/ kg/day for 6 days) plus fractionated irradiation (XRT; 2 Gy/day for 4 days), compared to XRT (2 Gy/day for 4 days) alone. No enhancement in the radiation response of HT29 s.c. xenografts was found with continuous infusion IUdR (100 mg/kg/day for 6 days) plus XRT (2 Gy/day for 4 days), compared to XRT alone. Using cytosolic extracts from normal human liver specimens, we found a rapid (15-mm) conversion of IPdR to IUdR. Coincubation of liver cytosol with IPdR and allopurinol, an inhibitor of xanthine oxidase, had no inhibitory effect on IPdR metabolism, whereas coincubation with IPdR and isovaniffin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significanfly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of LPdR was found in cytosolic extracts from colorectab liver metastases in two patients and from the HT29 human colon cancer xenografts in athymic mice. These additional data indicate that IPdR has the potential for clinical use as a p.o. prodrug for IUdR-mediated radiosensitization of resistant human cancers.

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تاریخ انتشار 2005