• Jae Sung Kim, George P Amorino, Hongryull Pyo, Qianwen Cao, and Hak Choy.
• Department of Radiation Oncology, The Vanderbilt Clinic B-902, Vanderbilt University Medical Center, 1301 22nd Avenue S., Nashville, TN 37232-5671, USA.
• Radiother Oncol. 2002 Jan 1; 62 (1): 61-7.

Background And PurposeWe 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 MethodsH460 human lung carcinoma cells were plated and treated with 10nM RFS-2000 or 4.5microM CPT-11 for 4h. Cells were then irradiated with various doses and treated with 1microM etoposide for 1.5h. 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.ResultsSurvival 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.ConclusionsThese 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.

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