Mechanism of the radiosensitization induced by vinorelbine in human non-small cell lung cancer cells.
Vinorelbine (Navelbine, KW-2307), a semisynthetic vinca alkaloid, is a potent inhibitor of mitotic microtubule polymerization. The aims of this study were to demonstrate radiosensitization produced by vinorelbine in human non-small cell lung cancer (NSCLC) PC-9 cells and to elucidate the cellular mechanism of radiosensitization. A clonogenic assay demonstrated that PC-9 cells were sensitized to radiation by vinorelbine with a maximal sensitizer enhancement ratio at a 10% cell survival level of 1.35 after 24-h exposure to vinorelbine at 20 nM. After 24-h exposure to vinorelbine at 20 nM, the approximately 67% of the cells that had accumulated in the G2/M-phase were cultured in the absence of vinorelbine and then irradiated at a dose of 8 Gy. Flow cytometric analyses showed prolonged G2/M accumulation concomitant with continuous polyploidization, and induction of apoptosis was observed in the cells subjected to the combination of vinorelbine-pretreatment and radiation. Polyploidization and induction of apoptosis were confirmed by morphological examination and a DNA fragmentation assay, respectively. We concluded that vinorelbine at a minimally toxic concentration moderately sensitizes human NSCLC cells to radiation by causing accumulation of cells in the G2/M-phase of the cell cycle. Prolonged G2/M accumulation concomitant with continuous polyploidization and increased susceptibility to induction of apoptosis may be associated with the cellular mechanism of radiosensitization produced by vinorelbine.
Fukuoka
K
K
Pharmacology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Arioka
H
H
Iwamoto
Y
Y
Fukumoto
H
H
Kurokawa
H
H
Ishida
T
T
Tomonari
A
A
Suzuki
T
T
Usuda
J
J
Kanzawa
F
F
Saijo
N
N
Nishio
K
K
D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077235:Vinorelbine
D004273:DNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D014747:Vinblastine; D000077235:Vinorelbine