Radiosensitization of vinorelbine and gemcitabine in NCI-H460 non-small-cell lung cancer cells.
OBJECTIVE
Results from recent clinical studies of gemcitabine and vinorelbine have encouraged the use of this combination concurrently with radiotherapy in the treatment of non-small-cell lung cancer, although preclinical data are limited. The present study aimed to quantify the in vitro interaction and radiosensitizing effect of gemcitabine and vinorelbine individually and in combination.


METHODS
Cytotoxicity was measured by exposing NCI-H460 cells to gemcitabine and/or vinorelbine simultaneously or sequentially, followed by irradiation at 0-10 Gy. Clonogenic cell survival assays were performed. Flow cytometry was used to measure the effects of both drug and radiation on cell cycle distribution. Apoptosis was assessed by morphologic criteria, by sub-G1 changes using flow cytometry assay, and by Annexin-V binding assay.


RESULTS
Both drugs showed single-agent activity against NCI-H460 cells and targeted different phases of the cell cycle. When both drugs were used in combination, they showed schedule-dependent interaction. An antagonistic effect was observed with simultaneous exposure to the two drugs. The optimum combination schedule was sequential exposure to vinorelbine followed by gemcitabine 24 h later. Both drugs showed radiosensitization effects. The radiosensitization effect of gemcitabine was evident when radiation was given immediately after 4-h incubation. However, the radiosensitization effect of vinorelbine was time dependent and observed with radiation given at 24 h postincubation. Apoptosis induced by gemcitabine increased gradually, reaching 20% at 72 h posttreatment. In contrast, apoptotic cell death was an early feature in vinorelbine-treated cells, reaching approximately 40% at 24 h.


CONCLUSIONS
The individual cytotoxic effects of gemcitabine and vinorelbine on NCI-H460 cells are phase specific, and the combined effect of gemcitabine and vinorelbine is sequence dependent. The radiosensitizing effects of both drugs seem to be related to enhanced apoptosis.
Zhang
Mei
M
Department of Radiation Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. mzhang@email.cs.nsw.gov.au
Boyer
Michael
M
Rivory
Laurent
L
Hong
Angela
A
Clarke
Stephen
S
Stevens
Graham
G
Fife
Kate
K
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000077235:Vinorelbine; D000093542:Gemcitabine
D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D014747:Vinblastine; D000077235:Vinorelbine; D000093542:Gemcitabine