The role of apoptosis in 2',2'-difluoro-2'-deoxycytidine (gemcitabine)-mediated radiosensitization.
The nucleoside analogue Gemcitabine [2',2'-difluoro-2'-deoxycytidine (dFdCyd)] is active against a wide variety of solid tumors and is a potent radiation sensitizer. Because apoptosis has been shown to be an important mechanism of cell death for many cancers, we wished to investigate the role of apoptosis in dFdCyd-mediated radiosensitization. We evaluated HT29 colon cancer cells, UMSCC-6 head and neck cancer cells, and A549 lung cancer cells, which differ substantially in the ability to undergo radiation-induced apoptosis. We hypothesized that if dFdCyd produced radiosensitization by potentiating preexisting death pathways, then only the apoptotic-prone HT29 cells would show a substantial increase in apoptosis when treated with the combination of dFdCyd and radiation and that UMSCC-6 cells and A549 cells would be radiosensitized through nonapoptotic mechanisms. We found that the radiosensitization of HT29 cells (enhancement ratio, 1.81 +/- 0.16) was accompanied by an increase in apoptosis and by caspase activation and that inhibition of this activation by the caspase inhibitor Z-Asp-Glu-Val-Asp-fluoromethylketone (DEVD) significantly decreased radiosensitization (to 1.36 +/- 0.24; P < 0.05). In contrast, UMSCC-6 cells and A549 cells were modestly radiosensitized (enhancement ratio, 1.47 +/- 0.24 and 1.31 +/- 0.04, respectively) via a nonapoptotic mechanism. These findings suggest that although apoptosis can contribute significantly to dFdCyd-mediated radiosensitization, the role of apoptosis in dFdCyd-mediated radiosensitization depends on the cell line rather than representing a general property of the drug.
Lawrence
T S
TS
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor 48109-0582, USA. tsl@umich.edu
Davis
M A
MA
Hough
A
A
Rehemtulla
A
A
D017209:Apoptosis / Q000528:radiation effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000528:radiation effects; D003037:Cobalt Radioisotopes; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D003374:Coumarins / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000528:radiation effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D016521:Electrophoresis, Gel, Pulsed-Field; D004789:Enzyme Activation / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D009842:Oligopeptides / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D000093542:Gemcitabine
D061945:Caspase Inhibitors; D003037:Cobalt Radioisotopes; D003374:Coumarins; D004273:DNA, Neoplasm; D009842:Oligopeptides; D011838:Radiation-Sensitizing Agents; C115495:aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; D003841:Deoxycytidine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000093542:Gemcitabine