Sensitization of cells to x-ray by 5-chloro-2'-deoxycytidine: studies on the metabolism and incorporation in DNA of a novel radiosensitizer

Thesis/Dissertation · Tue Jan 01 04:00:00 EST 1985

OSTI ID:5885912

Perez, L M

Rapid catabolism and generalized toxicity have limited the use of 5-halogenated deoxyuridine analogs as tumor radiosensitizers. This problem was approached by utilizing a deoxycytidine analog, 5-chloro-2'-deoxycytidine (CldC) coadministered with tetrahydrouridine (H/sub 4/U), an inhibitor of its deamination. Enzyme kinetic data and studies in various cell lines indicate that CldC + H/sub 4/U may be metabolized as follows: CldC ..-->.. CldCMP ..-->.. CldUMP ..-->.. ..-->.. CldUTP ..-->.. DNA ((1) deoxycytidine kinase; (2) deoxycytidylate deaminase dCMPD; (3) thymidylate kinase; and (4) DNA polymerase). All of these enzymes are elevated in human and mouse malignant tumors above that of normal tissues; especially dCMPD, which is elevated 20- to 80-fold. In tumors high in cytidine deaminase (CD), the following pathway is also likely involved: CldC ..-->.. CldU ..-->.. CldUMP ..-->.. ..-->.. CldUTP ..-->.. DNA ((1) Cd and (2) thymidine kinase). It is not known whether one of these two pathways (Cd ..-->.. TK or dCK ..-->.. dCMPD) is preferred in tumors. CldC + H/sub 4/U sensitized cells (HEp-2, S-180 and RIF-1) to X-ray and was incorporated in DNA as CldU at a substitution level of 20 to 30%. CHO cells, which intrinsically lack both CD and dCMPD were sensitized by CldU but displayed only marginal X-ray sensitization with CldC + H/sub 4/U. Thus, both pathways of conversion (dCK ..-->.. dCMPD; CD ..-->.. TK) of CldC to CldUMP cannot be blocked.

• Research Organization: Miami Univ., Coral Gables, FL (USA)
• OSTI ID: 5885912
• Country of Publication: United States
• Language: English

Related Subjects

560121* -- Radiation Effects on Cells-- External Source-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMIDINASES
ANIMAL CELLS
AZINES
BIOLOGICAL PATHWAYS
CHO CELLS
DEOXYCYTIDINE
DNA
DNA POLYMERASES
ELECTROMAGNETIC RADIATION
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROLASES
IONIZING RADIATIONS
METABOLISM
NON-PEPTIDE C-N HYDROLASES
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
NUCLEOTIDYLTRANSFERASES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
POLYMERASES
PYRIMIDINES
RADIATIONS
RADIOSENSITIVITY
RADIOSENSITIVITY EFFECTS
RIBOSIDES
TRANSFERASES
TUMOR CELLS
X RADIATION