EFFECT OF DOSE REGIMEN ON THE TOXICITY OF 2'-DEOXY-2'-METHYLIDENECYTIDINE (DMDC) IN MONKEYS
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概要
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2'-Deoxy-2'-methylidenecytidine (DMDC) is a potential anticancer deoxycytidine analog of cytosine arabinoside. Using monkeys, we conducted a 4-week toxicity study with toxicokinetics of DMDC at 1, 3, and 10mg/kg/day and a dose-regimen study of three different schedules of once-daily administration (5mg/kg/day) for 1 week every 2 weeks, 2 weeks every 4 weeks, and 3 weeks every 4 weeks. Deaths, myelosuppression, intestinal toxicity, and swelling of palm and sole skin were observed by oral DMDC treatment at 10mg/kg/day in 4-week repeated toxicity study; however, no skin disorders have been reported in humans. No notable changes were observed at 1 and 3mg/kg/day. The curves of dose vs. AUC and the AUC at MTD in monkey are similar to those in humans. In the dose-regimen study, all the toxicities were reversible but more severe toxicity was observed with the longer administration periods. One-week interruption showed sufficient recovery of decreased WBC in dosing regimens of 1-week-on/1-week-off and 2-weeks-on/2-weeks-off. A2-week recovery period was almost sufficient for the recovery of decreased RBC, HCT, and skin disorders in the 2-weeks-on/2-weeks-off regimen. Therefore, once-daily for 2 weeks every 4 weeks was concluded to be the optimal dose regimen. In summary, myelosuppression, intestinal toxicity, and skin disorders were observed in DMDC treatment in monkeys, the relationship between AUC and toxicity in monkeys was close to that in humans, and in preclinical studies, it is advantageous to investigate optimal dose regimens using the appropriate species.
- 日本トキシコロジー学会の論文
- 2007-10-15
著者
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Kobayashi Kazuko
Research Compliance & Quality Assurance Coordination Department Research Division Chugai Pharmac
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SHINDOH Hidetoshi
Pre-clinical Research Department
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KAWASHIMA Akira
Safety Assessment Department
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SHISHIDO Nobuyuki
Safety Assessment Department
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NAKANO Kounosuke
Pre-clinical Research Department
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HORII Ikuo
Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc.
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Horii Ikuo
Showa Univ. (department Of Biochemical Toxicology School Of Pharmaceutical Sciences)
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Horii Ikuo
Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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Horii Ikuo
Worldwide Safety Sciences Pgrd Nagoya Laboratories Pfizer Inc.
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Horii Ikuo
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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Nakano Kohnosuke
Pre-clinical Research Department Research Division Chugai Pharmaceutical Co. Ltd.
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Nakano Kounosuke
Pre-clinical Research Department Research Division Chugai Pharmaceutical Co. Ltd. Fuji Gotemba Resea
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Shishido Nobuyuki
Safety Assessment Department Research Division Chugai Pharmaceutical Co. Ltd.
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Shishido Nobuyuki
Safety Assessment Department Research Division Chugai Pharmaceutical Co. Ltd. Fuji Gotemba Research
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Shindoh Hidetoshi
Department Of Toxicology And Pathology Department Of Pharmacokinetics And Metabolism Nippon Roche Re
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Kobayashi Kazuko
Research Compliance & Quality Assurance Coordination Department Research Division Chugai Pharmac
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Kawashima Akira
Department Of Toxicology And Pathology Department Of Pharmacokinetics And Metabolism Nippon Roche Re
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Horii Ikuo
Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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Shindoh Hidetoshi
Pre-clinical Res. Dep. Res. Div. Chugai Pharmaceutical Co. Ltd. Kamakura Res. Labs.
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