Radiosensitization by thymidine phosphorylase inhibitor in thymidine phosphorylase negative and overexpressing bladder cancer cell lines.

Abstract

TAS-102 (trifluorothymidine [TFT] and thymidine phosphorylase inhibitor [TPI] in a molar ratio of 1:0.5) has activity in 5-fluorouracil resistant colon cancer. TPI is added to increase TFT's bioavailability. TFT has a dual mechanism of action by inhibiting thymidylate synthase and by its incorporation into DNA. Interesting radiosensitizing effects of TPI were recently reported. The aim of our study was to determine whether TP expression would affect radiosensitivity and to characterize the effect of TPI. Two bladder cancer cell lines RT112 (TP negative) and RT112/TP (TP overexpression) were tested for drug sensitivity and radiosensitivity (clonogenic assay), with and without TFT and/or TPI. Expression of γ H2AX was used as marker for DNA damage. RT112 cells were not more sensitive to TFT then RT112/TP cells. TPI alone did not inhibit cell growth of RT112 even at 100 μM, but inhibited that of RT112/TP by 27%. In both RT112 and RT112/TP cells 10 μM TPI did not or slightly affect radiosensitivity, but 100 μM TPI alone enhanced the radiation response (p<.05). TFT alone at 1 μM and in combination with 10 μM TPI did not affect the radiation response of both cell lines. TPI alone induced expression of ϒH2AX, which was increased in combination with radiation. In conclusion, TPI enhanced radiosensitivity at high concentrations, independent of TP expression, while TFT and TPI at a low concentration did not affect the radiosensitivity of RT112 and RT112/TP cell lines.

• Authors: Maha El-Naggar, Eva Ebbing, Irene Bijnsdorp, Jaap van den Berg, Godefridus J Peters
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 33 Issue 4-6 Pg. 413-21 ( 2014) ISSN: 1532-2335 [Electronic] United States
• PMID: 24940699 (Publication Type: Journal Article)

Chemical References

• Drug Combinations
• Enzyme Inhibitors
• Pyrrolidines
• Radiation-Sensitizing Agents
• trifluridine tipiracil drug combination
• Uracil
• Thymidine Phosphorylase
• Thymine
• Trifluridine

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects, radiation effects)
• DNA Damage
• Drug Combinations
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Humans
• Pyrrolidines
• Radiation-Sensitizing Agents (pharmacology)
• Thymidine Phosphorylase (antagonists & inhibitors, deficiency, metabolism)
• Thymine
• Trifluridine (pharmacology)
• Uracil (analogs & derivatives, pharmacology)
• Urinary Bladder Neoplasms (pathology)