Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was recently reported to be converted to 5-iodo-2'-deoxyuridine (IUdR) by an aldehyde oxidase, most concentrated in liver tissue. We questioned whether IPdR could be used as a p.o. hepatotropic prodrug to increase the percentage of IUdR-DNA incorporation into liver tumors compared to normal liver with acceptable systemic toxicity. Athymic nude mice with human colon cancer (HCT-116) xenograft tumors as liver metastases and s.c. flank tumors received daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 days. The maximum tolerated dose of IUdR was 250 mg/kg/day and was associated with a > 10% weight loss and a high percentage of IUdR-DNA incorporation (> 5%) into normal bone marrow and intestine. In contrast, animals tolerated escalating doses of IPdR to 1 gm/kg/day without weight loss and with less (1.5-4%) IUdR-DNA incorporation in normal tissues. Pharmacokinetic analysis of p.o. IPdR showed peak plasma levels of IPdR and IUdR within 15-45 min, suggesting efficient conversion of IPdR to IUdR. Aldehyde oxidase activity was found in normal liver tissue but not in other normal or tumor tissues. Additionally, we found a 2-3 times greater percentage of IUdR-DNA incorporation in tumor with IPdR than IUdR at the highest doses used. However, no differential effect in the percentage of IUdR-DNA incorporation was noted between liver metastases and s.c. tumors with either IPdR or IUdR. We conclude that p.o. IPdR offers a greater therapeutic index for tumor incorporation (and presumably radiosensitization) than a similar schedule of IUdR.
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PMID:An in vivo comparison of oral 5-iodo-2'-deoxyuridine and 5-iodo-2-pyrimidinone-2'-deoxyribose toxicity, pharmacokinetics, and DNA incorporation in athymic mouse tissues and the human colon cancer xenograft, HCT-116. 816 99

We reported previously that p.o. administered 5-iodo-2-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 cytosolic 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 (< or = 10% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 microM at 10 min 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 (< or = 1% in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 g/kg/day 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 IUdR levels were 1.0-1.2 microM 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-min) 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 isovanillin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significantly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of IPdR was found in cytosolic extracts from colorectal 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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PMID:Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues. 951 58

IPdR (5-iodo-2-pyrimidinone-2'-deoxyribose) is a novel orally available, halogenated thymidine (TdR) analog and is a potential radiosensitizer for use in human tumors, such as rectal, pancreas, sarcoma and glioma tumors. IPdR is a prodrug that is efficiently converted to IUdR (5-iodo-2'-deoxyuridine), an intravenous radiosensitizer by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or = 1 h after oral IPdR. Athymic mice tolerated oral IPdR to doses up to 1500 mg/kg/day t.i.d. for 6 - 14 days without significant systemic toxicities. A number of in vivo preclinical studies have demonstrated that IPdR is a superior radiosensitizer compared with IUdR given as a continuous infusion in terms of safety and efficacy with a significantly lower toxicity profile, including gastrointestinal and hematologic side effects. A preclinical study has shown that IPdR is effective in inducing human colon cancer xenograft radiosensitization in drug-resistant DNA mismatch repair-proficient and -deficient tumor models, as well as in human globlastoma xenograft. In anticipation of performing a clinical Phase I trial in humans, investigators also studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species during a 14-day treatment course. Dose-limiting systemic toxicities (diarrhea, emesis, weight loss and decreased motor activity) were observed in ferrets receiving IPdR at 1500 mg/kg/day on a 14-day schedule that were not found previously in athymic mice. Recently, a once-daily IPdR dosing up to 2000/mg/kg for 28 days in Fischer-344 rats showed reversible mild-to-moderate systemic toxicities without any severe or life-threatening toxicities. However, in all preclinical toxicity studies so far, no significant hematologic, biochemical or histopathologic changes have been found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent fashion in the ferret liver, suggesting partial enzyme inactivation by this IPdwR schedule, but that is not found in Fischer-344 rats. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance are similar to previously published data in athymic mice. In this paper, the authors review the development, mechanism of action, preclinical data and rationale for clinical studies.
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PMID:IPdR: a novel oral radiosensitizer. 1771 27