TY - JOUR
T1 - Radiation enhancement by the combined use of topoisomerase I inhibitors, RFS-2000 or CPT-11, and topoisomerase II inhibitor etoposide in human lung cancer cells
AU - Kim, Jae Sung
AU - Amorino, George P.
AU - Pyo, Hongryull
AU - Cao, Qianwen
AU - Choy, Hak
N1 - Funding Information:
This study was supported by NIH grant CA 82117-02 and a grant from SuperGen, Inc. (Dublin, CA 94568, USA).
PY - 2002
Y1 - 2002
N2 - Background and purpose: We have tested the camptothecin analogs, RFS-2000 or CPT-11, in combination with both etoposide and ionizing radiation in vitro to examine the radiation enhancing potential of topoisomerase I plus topoisomerase II (Topo I + Topo II) inhibition in human cancer cells. Materials and methods: H460 human lung carcinoma cells were plated and treated with 10 nM RFS-2000 or 4.5 μM CPT-11 for 4 h. Cells were then irradiated with various doses and treated with 1 μM etoposide for 1.5 h. Cell survival and sublethal damage recovery (SLDR) were determined by clonogenic assay. 7-aminoactinomycin D (7-AAD) staining and flow cytometry were used to analyze cell viability/apoptosis after combined treatment of drugs with radiation. Results: Survival experiments showed radiation dose enhancement ratios (DER) of 1.26, 1.34, and 1.63 for RFS-2000, etoposide, and RFS-2000 plus etoposide, respectively; the corresponding DER values were 1.30, 1.39, and 1.65 for CPT-11, etoposide, and CPT-11 plus etoposide. The analysis of cell viability/apoptosis using 7-AAD staining and flow cytometry showed an additive effect. Greater inhibition of SLDR was observed with RFS-2000 plus etoposide than with either agent separately, but CPT-11 plus etoposide showed a more modest effect upon SLDR. Conclusions: These data show that the combination of Topo I inhibitors, RFS-2000 or CPT-11 plus Topo II inhibitor etoposide, is a more effective radiation enhancer than either agent alone in human lung cancer cells. The mechanism of radiation enhancement may involve inhibition of SLDR with RFS-2000 plus etoposide, but other mechanisms may be involved in the combined treatment including CPT-11.
AB - Background and purpose: We have tested the camptothecin analogs, RFS-2000 or CPT-11, in combination with both etoposide and ionizing radiation in vitro to examine the radiation enhancing potential of topoisomerase I plus topoisomerase II (Topo I + Topo II) inhibition in human cancer cells. Materials and methods: H460 human lung carcinoma cells were plated and treated with 10 nM RFS-2000 or 4.5 μM CPT-11 for 4 h. Cells were then irradiated with various doses and treated with 1 μM etoposide for 1.5 h. Cell survival and sublethal damage recovery (SLDR) were determined by clonogenic assay. 7-aminoactinomycin D (7-AAD) staining and flow cytometry were used to analyze cell viability/apoptosis after combined treatment of drugs with radiation. Results: Survival experiments showed radiation dose enhancement ratios (DER) of 1.26, 1.34, and 1.63 for RFS-2000, etoposide, and RFS-2000 plus etoposide, respectively; the corresponding DER values were 1.30, 1.39, and 1.65 for CPT-11, etoposide, and CPT-11 plus etoposide. The analysis of cell viability/apoptosis using 7-AAD staining and flow cytometry showed an additive effect. Greater inhibition of SLDR was observed with RFS-2000 plus etoposide than with either agent separately, but CPT-11 plus etoposide showed a more modest effect upon SLDR. Conclusions: These data show that the combination of Topo I inhibitors, RFS-2000 or CPT-11 plus Topo II inhibitor etoposide, is a more effective radiation enhancer than either agent alone in human lung cancer cells. The mechanism of radiation enhancement may involve inhibition of SLDR with RFS-2000 plus etoposide, but other mechanisms may be involved in the combined treatment including CPT-11.
KW - CPT-11
KW - Etoposide
KW - Lung cancer
KW - RFS-2000
KW - Radiation
UR - http://www.scopus.com/inward/record.url?scp=0036159856&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036159856&partnerID=8YFLogxK
U2 - 10.1016/S0167-8140(01)00465-0
DO - 10.1016/S0167-8140(01)00465-0
M3 - Article
C2 - 11830313
AN - SCOPUS:0036159856
SN - 0167-8140
VL - 62
SP - 61
EP - 67
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
IS - 1
ER -