Abstract
<p>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 tetrahydro- uridine (H(,4)U), an inhibitor of its deamination. Enzyme kinetic dataand studies in various cell lines indicate that CldC + H(,4)U may be metabolized as follows: (UNFORMATTED TABLE FOLLOWS)1 2 3 4CldC (--->) CldCMP (--->) CldUMP (--->) (--->) CldUTP (--->) DNA(TABLE ENDS)((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- to80-fold. In tumors high in cytidine deaminase (CD), the following pathway is also likely involved: (UNFORMATTED TABLE FOLLOWS)1 2CldC (--->) CldU (--->) CldUMP (--->) (--->) CldUTP (--->) DNA(TABLE ENDS)((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(,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(,4)U. Thus, both pathways of conversion (dCK (--->) dCMPD; CD (--->) TK) of CldC to CldUMP cannot be blocked.Incorporation of CldC as such in DNA was not detected () FdC (60 mg/kg) + H(,4)U (50 mg/kg) --6h(--->) ('14)C-CldC (200 mg/kg) + H(,4)U (50 mg/kg) demonstrated that animals receiving this treatment incorporate more CldU in Sarcoma-180 tumor DNA than mice receiving only CldC + H(,4)U. PALA and FdC + H(,4)U treatments appear to enhance the selective incorporation of CldU in tumors as compared to normal tissue. The selectivity of this strategy for the radiosensitization of tumors goes beyond the exploitation of growth kinetic differences between normal and neoplastic tissues; by taking advantage of differences in enzyme levels between those tissues, preferential conversion of CldC to CldUTP in tumors may be achieved.</p>