Na+, K+-ATPase inhibitor, ouabain accentuates irradiation damage in human tumour cell lines.
Two normal, two tumour, one transformed fibroblast cell line established from Ataxia telangiectasia (AT) patients and one corrected AT hybrid were characterised with regard to alpha, beta, SF2, and D values. Survival of 60Co gamma-irradiated tumour and transformed cells was markedly reduced when the Na+, K+-ATPase inhibitor ouabain was present 1 hr before and 3 hr post irradiation. Under these conditions, the radiosensitivity in normal cells remained virtually unchanged. Suppression of repair was found to play a role in the ouabain-induced inhibition of the cell survival. In A549 lung carcinoma cells, addition of 10(-8) M ouabain decreases the sublethal damage recovery ratio from 56.5 to 13.3. The same drug concentration decreases the recovery ratio in L132 epithelial cells only from 5.1 to 4.9. The fast repair component, as measured over the first 1.5 hr after irradiation, decreases from 1.83 to 0.36 hr(-1) in A549 cells and from 0.35 to 0.16 hr(-1) in HeLa cells. For 2 Gy fractions, the presence of 10(-8) M ouabain 1 hr before irradiation and 3 hr after irradiation induces dose enhancement ratios of 1.15-1.5. A more pronounced effect on cell inactivation may be expected from multiple fractions. The concentrations required to downregulate sublethal damage repair fall within the range where cardiac glycosides are used clinically. Application of these drugs in radiotherapy thus seems feasible.
Verheye-Dua
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Radiation Oncology Department, Stellenbosch University, Tygerberg, South Africa. FAAV@maties.sun.ac.za
Böhm
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D002461:Cell Line, Transformed / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D010042:Ouabain / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase