Radiation, pool size and incorporation studies in mice with 5-chloro-2′-deoxycytidine

• Published in: International journal of radiation oncology, biology, physics Vol. 19; no. 2; pp. 357 - 365
• Main Authors: Santos, Orlando, Perez, Liliana M, Briggle, Thomas V, Boothman, David A, Greer, Sheldon B
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.1990; Elsevier
• Subjects: 5-Benzylacyclouridine; 5-Fluorodeoxycytidine; Animals; Aspartic Acid - analogs & derivatives; Aspartic Acid - therapeutic use; Biological and medical sciences; Combined Modality Therapy; Cytidine Deaminase - antagonists & inhibitors; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacokinetics; Deoxycytidine - therapeutic use; DNA, Neoplasm - metabolism; Drug Therapy, Combination; Halogenated deoxycytidine analogues; Medical sciences; Mice; Mice, Inbred C3H; N-(Phosphonacetyl)-L-aspartic acid; Phosphonoacetic Acid - analogs & derivatives; Phosphonoacetic Acid - therapeutic use; Radiation-Sensitizing Agents - pharmacokinetics; Radiation-Sensitizing Agents - therapeutic use; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Sarcoma, Experimental - drug therapy; Sarcoma, Experimental - metabolism; Sarcoma, Experimental - radiotherapy; Tetrahydrouridine; Tetrahydrouridine - therapeutic use; Uracil - analogs & derivatives; Uracil - therapeutic use; Uridine Phosphorylase - antagonists & inhibitors; Halogenated deoxycytidine analogues; N-(Phosphonacetyl)-L-aspartic acid; Tetrahydrouridine; 5-Fluorodeoxycytidine; 5-Benzylacyclouridine; Cell line; Radiosensitivity; Treatment; Animal; Malignant tumor; Radiotherapy; X ray irradiation; Tumor cell
• DOI: 10.1016/0360-3016(90)90544-T
• ISSN: 0360-3016

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 BDF 1 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 (H 4U), a potent inhibitor of cytidine deaminase, can effectively inhibit the enzyme in the normal tissues of BDF 1 mice. When H 4U 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.