Mechanism of the radiosensitization induced by vinorelbine in human non-small cell lung cancer cells

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 34; no. 3; pp. 451 - 460
• Main Authors: Fukuoka, Kazuya, Arioka, Hitoshi, Iwamoto, Yasuo, Fukumoto, Hisao, Kurokawa, Hirokazu, Ishida, Tomoyuki, Tomonari, Akira, Suzuki, Toshihiro, Usuda, Jitsuo, Kanzawa, Fumihiko, Saijo, Nagahiro, Nishio, Kazuto
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.12.2001; Elsevier Science
• Subjects: Apoptosis; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - radiotherapy; Cell Cycle - drug effects; DNA Damage - drug effects; DNA Damage - radiation effects; DNA, Neoplasm - drug effects; DNA, Neoplasm - radiation effects; Flow Cytometry; G2/M accumulation; Humans; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Medical sciences; Non-small cell lung cancer; Pneumology; Polyploidization; Radiation-Sensitizing Agents - pharmacology; Radiosensitization; Tumor Cells, Cultured; Tumors of the respiratory system and mediastinum; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Vinorelbine; Radiosensitization; G2/M accumulation; Vinorelbine; Non-small cell lung cancer; Polyploidization; Apoptosis; Human; Cell culture; Phase; Prognosis; Lung; Exposure; Malignant tumor; Survival; Accumulation; Mechanism; Assay; Alkaloid; Inhibitor; Level; Ratio; Sensitization; Microtubule; Small cell carcinoma; Cell; Sensitizer
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/S0169-5002(01)00265-3

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.