TY - JOUR
T1 - Radiation, pool size and incorporation studies in mice with 5-chloro-2′-deoxycytidine
AU - Santos, Orlando
AU - Perez, Liliana M.
AU - Briggle, Thomas V.
AU - Boothman, David A.
AU - Greer, Sheldon B.
N1 - Funding Information:
This study was supported by grants CA 37791 and CA 332 19 from the National Cancer Institute and a grant from the Florida High Technology and Industrial Council to S. Greer. Accepted for publication 22 February 1990.
PY - 1990/8
Y1 - 1990/8
N2 - Bolus doses of 5-chlorodeoxycytidine (CldC) administered with modulators of pyrimidine metabolism, followed by X-irradiation, resulted in a 2-fold dose increase effect against RIF-1 tumors in C3H mice. Pool size studies of the fate of [14-C]-CldC in BDF1 mice bearing Sarcoma-180 tumors, which demonstrated the rapid formation of 5-chlorodeoxycytidylate (CldCMP), and incorporation of CldC as such in RIF-1 tumor DNA, indicate that CldC is a substrate for deoxycytidine kinase, as our past Km studies have shown. Our data indicate that 5-chlorodeoxyuridine triphosphate (CldUTP) accumulates from both the cytidine deaminase-thymidine kinase pathway, as well as from the deoxycytidine kinase-dCMP deaminase pathway, in tumor tissue. As shown in a previous study, tetrahydrouridine (H4U), a potent inhibitor of cytidine deaminase, can effectively inhibit the enzyme in the normal tissues of BDF1 mice. When H4U was administered with the modulators N-(phosphonacetyl)-L-aspartic acid (PALA) and 5-fluorodeoxycytidine (FdC), the levels of CldC-derived RNA and DNA directed metabolites increased in tumor and decreased in normal tissues compared to when CIdC was administered alone. These modulators inhibit the de novo pathway of thymidine biosynthesis, lowering thymidine triphosphate (TTP) levels, which compete with CldUTP for incorporation into DNA. 5-Benzylacyclouridine (BAU), an inhibitor of uridine phosphorylase, was also utilized. DNA incorporation studies using C3H mice bearing RIF-1 tumors showed that the extent of incorporation of 5-chlorodeoxyuridine (CldU) into DNA correlates with the levels of cytidine and dCMP deaminases; this is encouraging in view of their high activity in many human malignancies and the low activities in normal tissues, including those undergoing active replication. Up to 3.9% replacement of thymidine by CldU took place in RIF-1 tumors, whereas incorporation into bone marrow was below our limit of detection. CldC did not result in photosensitization under conditions in cell culture in which radiosensitization to X rays was obtained. Thus, the combination of CldC with modulators of its metabolism has potential as a modality of selective radiosensitization for ultimate clinical use in a wider range of tumors than those of the brain.
AB - Bolus doses of 5-chlorodeoxycytidine (CldC) administered with modulators of pyrimidine metabolism, followed by X-irradiation, resulted in a 2-fold dose increase effect against RIF-1 tumors in C3H mice. Pool size studies of the fate of [14-C]-CldC in BDF1 mice bearing Sarcoma-180 tumors, which demonstrated the rapid formation of 5-chlorodeoxycytidylate (CldCMP), and incorporation of CldC as such in RIF-1 tumor DNA, indicate that CldC is a substrate for deoxycytidine kinase, as our past Km studies have shown. Our data indicate that 5-chlorodeoxyuridine triphosphate (CldUTP) accumulates from both the cytidine deaminase-thymidine kinase pathway, as well as from the deoxycytidine kinase-dCMP deaminase pathway, in tumor tissue. As shown in a previous study, tetrahydrouridine (H4U), a potent inhibitor of cytidine deaminase, can effectively inhibit the enzyme in the normal tissues of BDF1 mice. When H4U was administered with the modulators N-(phosphonacetyl)-L-aspartic acid (PALA) and 5-fluorodeoxycytidine (FdC), the levels of CldC-derived RNA and DNA directed metabolites increased in tumor and decreased in normal tissues compared to when CIdC was administered alone. These modulators inhibit the de novo pathway of thymidine biosynthesis, lowering thymidine triphosphate (TTP) levels, which compete with CldUTP for incorporation into DNA. 5-Benzylacyclouridine (BAU), an inhibitor of uridine phosphorylase, was also utilized. DNA incorporation studies using C3H mice bearing RIF-1 tumors showed that the extent of incorporation of 5-chlorodeoxyuridine (CldU) into DNA correlates with the levels of cytidine and dCMP deaminases; this is encouraging in view of their high activity in many human malignancies and the low activities in normal tissues, including those undergoing active replication. Up to 3.9% replacement of thymidine by CldU took place in RIF-1 tumors, whereas incorporation into bone marrow was below our limit of detection. CldC did not result in photosensitization under conditions in cell culture in which radiosensitization to X rays was obtained. Thus, the combination of CldC with modulators of its metabolism has potential as a modality of selective radiosensitization for ultimate clinical use in a wider range of tumors than those of the brain.
KW - 5-Benzylacyclouridine
KW - 5-Fluorodeoxycytidine
KW - Halogenated deoxycytidine analogues
KW - N-(Phosphonacetyl)-L-aspartic acid
KW - Tetrahydrouridine
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U2 - 10.1016/0360-3016(90)90544-T
DO - 10.1016/0360-3016(90)90544-T
M3 - Article
C2 - 2394614
AN - SCOPUS:0025127349
SN - 0360-3016
VL - 19
SP - 357
EP - 365
JO - International journal of radiation oncology, biology, physics
JF - International journal of radiation oncology, biology, physics
IS - 2
ER -