Abstract
A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Capecitabine
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / metabolism
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Cytidine Deaminase / metabolism
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Deoxycytidine / administration & dosage*
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Deoxycytidine / analogs & derivatives*
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Deoxycytidine / chemical synthesis*
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Deoxycytidine / pharmacokinetics*
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Dihydrouracil Dehydrogenase (NADP)
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Drug Design
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Drug Stability
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Esterases / metabolism
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Female
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Fluorouracil / blood
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Fluorouracil / pharmacokinetics
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Mice
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Oxidoreductases / antagonists & inhibitors*
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Prodrugs / administration & dosage
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Prodrugs / chemical synthesis*
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Prodrugs / pharmacokinetics*
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Thymidine Phosphorylase / metabolism
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Tissue Distribution
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Uracil / analogs & derivatives*
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Uracil / pharmacokinetics
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Uterine Cervical Neoplasms / drug therapy
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Uterine Cervical Neoplasms / metabolism
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Xenograft Model Antitumor Assays
Substances
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2',3'-O-diacetyl-5'-deoxy-5-vinylcytidine
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Prodrugs
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Deoxycytidine
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5-vinyluracil
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Uracil
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Capecitabine
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Oxidoreductases
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Dihydrouracil Dehydrogenase (NADP)
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Thymidine Phosphorylase
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Esterases
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Cytidine Deaminase
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Fluorouracil