Radiosensitization by gemcitabine.
Gemcitabine is a potent radiosensitizer in both laboratory studies and in the clinic. Initial laboratory studies showed that gemcitabine radiosensitizes a wide variety of rodent and human tumor cells in culture. Maximum radiosensitization occurs in cells that demonstrate concurrent redistribution into S phase and d-adenosine triphosphate pool depletion. Although the mechanism of sensitization is not yet clear, recent evidence from our laboratory suggests that gemcitabine lowers the threshold for radiation-induced apoptosis. Our preclinical data were used to design gemcitabine dose-escalation trials in combination with standard radiation for patients with unresectable head and neck cancer and pancreatic cancer. In head and neck cancer, we have found that gemcitabine doses far below the maximum tolerated dose for the drug when used alone significantly potentiate the toxicity of treatment. Comparatively, normal tissue sensitization has not been as marked in the treatment of pancreatic tumors. These findings have led us to conduct experiments using an animal model to improve the therapeutic index of treatment. We conclude that gemcitabine is a promising radiation sensitizer that will need to be developed cautiously if excessive normal tissue toxicity is to be avoided.
Lawrence
T S
TS
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, USA.
Eisbruch
A
A
McGinn
C J
CJ
Fields
M T
MT
Shewach
D S
DS
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine