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Potentiation of cytotoxicity and radiosensitization of (E)‐2‐deoxy‐2′‐(fluoromethylene) cytidine by pentoxifylline In vitro
Author(s) -
Li YeXiong,
Sun LinQuan,
WeberJohnson Kerstin,
Paschoud Nicolas,
Coucke Philippe A.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990105)80:1<155::aid-ijc27>3.0.co;2-a
Subject(s) - cytotoxicity , clonogenic assay , cytotoxic t cell , cytidine , cell cycle , ribonucleotide reductase , cancer research , paclitaxel , radiosensitizer , pharmacology , pentoxifylline , chemistry , in vitro , microbiology and biotechnology , biology , biochemistry , cell , radiation therapy , medicine , cancer , enzyme , genetics , protein subunit , gene
(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 G 2 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 IC 50 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 G 2 arrest, and such G 2 accumulation was also abrogated by PTX. These results suggest that pharmacological abrogation of S and G 2 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.