Potentiation of cytotoxicity and radiosensitization of (E)‐2‐deoxy‐2′‐(fluoromethylene) cytidine by pentoxifylline In vitro

• Published in: International journal of cancer Vol. 80; no. 1; pp. 155 - 160
• Main Authors: Li, Ye‐Xiong, Sun, Lin‐Quan, Weber‐Johnson, Kerstin, Paschoud, Nicolas, Coucke, Philippe A.
• Format: Journal Article Web Resource
• Language: English
• Published: New York John Wiley & Sons, Inc 05.01.1999; Wiley-Liss; Wiley Liss, Inc
• Subjects: anti-tumor; Antineoplastic agents; Antineoplastic Agents - toxicity; Biological and medical sciences; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Survival - drug effects; Cell Survival - radiation effects; Cesium Radioisotopes; Colonic Neoplasms; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); cytotoxic; Deoxycytidine - analogs & derivatives; Deoxycytidine - toxicity; DNA Damage; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; FMdC; G2 Phase; Hematology; Human health sciences; Humans; Hématologie; Medical sciences; novel inhibitor; Oncologie; Oncology; Pentoxifylline - toxicity; Pharmacology. Drug treatments; Radiation-Sensitizing Agents - toxicity; radiosensitizing; radiotherapy; S Phase; Sciences de la santé humaine; Tumor Cells, Cultured; Adenocarcinoma; Antineoplastic agent; Human; Drug combination; Cytotoxicity; Malignant tumor; In vitro; Colonic disease; Pentoxifylline; Ionizing irradiation; Radiosensitizing agent; Established cell line; Digestive diseases; Intestinal disease; Drug interaction; Combined treatment; Xanthine derivatives; Colon; Pyrimidine nucleoside
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19990105)80:1<155::AID-IJC27>3.0.CO;2-A

(E)‐2′‐deoxy‐2′‐(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide‐diphosphate reductase, has been shown to have anti‐tumor activity against solid tumors and sensitize tumor cells to ionizing radiation. Pentoxifylline (PTX) can potentiate the cell killing induced by DNA‐damaging agents through abrogation of DNA‐damage‐dependent G2 checkpoint. We investigated the cytotoxic, radiosensitizing and cell‐cycle effects of FMdC and PTX in a human colon‐cancer cell line WiDr. PTX at 0.25–1.0 mM enhanced the cytotoxicity of FMdC and lowered the IC50 of FMdC from 79 ± 0.1 to 31.2 ± 2.1 nM, as determined by MTT assay. Using clonogenic assay, pre‐irradiation exposure of exponentially growing WiDr cells to 30 nM FMdC for 48 hr or post‐irradiation to 0.5 to 1.0 mM PTX alone resulted in an increase in radiation‐induced cytotoxicity. Moreover, there was a significant change of the radiosensitization if both drugs were combined as compared with the effect of either drug alone. Cell‐cycle analysis showed that treatment with nanomolar FMdC resulted in S‐phase accumulation and that such an S‐phase arrest can be abrogated by PTX. Treatment with FMdC prior to radiation increased post‐irradiation‐induced G2 arrest, and such G2 accumulation was also abrogated by PTX. These results suggest that pharmacological abrogation of S and G2 checkpoints by PTX may provide an effective strategy for enhancing the cytotoxic and radiosensitizing effects of FMdC. Int. J. Cancer 80:155–160, 1999. © 1999 Wiley‐Liss, Inc.