Marked radiosensitization of cells in culture to x ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis

Conference · Wed Aug 01 04:00:00 EDT 1984 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

OSTI ID:6500575

Perez, L M; Mekras, J A; Briggle, T V; Greer, S

The authors approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine), which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC) with tetrahydrouridine (H/sub 4/U). They propose that CldC, coadministered with H/sub 4/U, is metabolized in the following manner: CldC ..-->.. CldCMP ..-->.. CldUMP ..-->.. ..-->.. CldUTP ..-->.. DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In x irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses. They obtained 3.0 to 3.8 apparent dose enhancement ratios when cells were preincubated with inhibitors of pyrimidine biosynthesis. Enzymatic studies indicate that this toxicity may be tumor selective. Preliminary toxicity studies indicate that mice will tolerate treatment protocols with marginal weight loss (4%). In this approach the authors seek to obtain preferential conversion of CldC to CldUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.

• Research Organization: Univ. of Miami, FL
• OSTI ID: 6500575
• Conference Information: Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Journal Volume: 10:8
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
560121* -- Radiation Effects on Cells-- External Source-- (-1987)
560152 -- Radiation Effects on Animals-- Animals
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIMETABOLITES
ANTIMICROBIAL AGENTS
AZINES
BIOCHEMISTRY
BIOSYNTHESIS
CELL KILLING
CHEMICAL REACTIONS
CHEMISTRY
DEAMINATION
DEOXYCYTIDINE
DRUGS
ELECTROMAGNETIC RADIATION
ENZYMES
FLUOROURACILS
FUDR
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
IONIZING RADIATIONS
MAMMALS
MICE
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC FLUORINE COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
PYRIMIDINES
RADIATIONS
RADIOINDUCTION
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
RIBOSIDES
RODENTS
SYNTHESIS
TRANSFERASES
TUMOR CELLS
URACILS
VERTEBRATES
X RADIATION