Metabolic activation and antineoplastic-selective mechanism of action of two novel fluoropyrimidines
The coadministration of tetrahydrouridine (H/sub 4/Urd) diverted the metabolism of /sup 3/H-5-fluoro-2'-deoxycytidine (FdCyd) in human epidermoid laryngeal carcinoma (HEp-2) cells through the deoxycytidine kinase-deoxycytidylate deaminase (dCK-dCMPD) pathway to the formation of 5-fluorodeoxyuridylate (FdUMP) without the incorporation of 5-fluorouridylate (FUMP) into RNA or the formation of RNA-level antimetabolite pools. Antimetabolite pool sizes, as assayed by HPLC, following treatment of BD2F/sub 1/ mice bearing ascitic mammary adenocarcinoma-755 (ADC-755) or Lewis lung carcinoma (LLC) with /sup 3/H-FdCyd + H/sub 4/ Urd resulted in pool sizes indicative of a tumor-selective, dual pathway metabolism of FdCyd via both the cytidine deaminase-deoxythymidine kinase (CD-dTK) and dCK-dCMPD pathways. In contrast to the high levels of all RNA- and DNA-level antimetabolites derived from FdCyd found in tumor tissue, in normal tissues (bone marrow, intestine, liver and spleen) and in serum, FdCyd was metabolized to only a small extent, all antimetabolite pools were markedly lower. /sup 3/H-FdCyd + H/sub 4/Urd exposure resulted in selective incorporation of antimetabolites into tumor RNA and DNA. dCMPD and CD enzyme assays have confirmed that H/sub 4/Urd administration effectively inhibited the low CD activity in normal, but not the elevated levels found in tumor tissue.
- Research Organization:
- Miami Univ., FL (USA)
- OSTI ID:
- 5514468
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTIMETABOLITES
METABOLIC ACTIVATION
FLUOROURACILS
TUMOR CELLS
BIOLOGICAL PATHWAYS
AMINOTRANSFERASES
CARCINOMAS
ENZYME ACTIVITY
LIQUID COLUMN CHROMATOGRAPHY
MICE
ORGANIC FLUORINE COMPOUNDS
PHOSPHOTRANSFERASES
PYRIMIDINES
TRITIUM COMPOUNDS
ANIMAL CELLS
ANIMALS
AZINES
CHROMATOGRAPHY
DISEASES
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
LABELLED COMPOUNDS
MAMMALS
NEOPLASMS
NITROGEN TRANSFERASES
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
RODENTS
SEPARATION PROCESSES
TRANSFERASES
URACILS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques