Effects of SN-38 (an active metabolite of CPT-11) on responses of human and rodent cells to irradiation.
OBJECTIVE
Modulators of the DNA-unwinding enzyme, topoisomerase I (Topo I), inhibit DNA repair and have been reported to increase the lethal effects of X rays, which create breaks in DNA. CPT-11 is a derivative of camptothecin, a Topo I inhibitor, and is clinically available. In this study, we tested the in vitro combination effects of SN-38, an active form of CPT-11, and irradiation on several cell lines.


METHODS
Exponentially growing or confluent cultures of CHO cells were treated with SN-38 for 30 min. Cells were then irradiated. Thereafter, the cells were further incubated with the drug for 0 to 3 h. Exponentially growing other cell lines were exposed to 200 nM SN-38 for 30 min before, during, and 3 h after irradiation. The cell survival rate was determined using a conventional clonogenic assay.


RESULTS
SN-38 (200 nM to 4 microM) alone showed slight toxicity to CHO cells in the confluent culture after a 3.5-h incubation. When the cells were treated with the lower doses of SN-38 (50 to 800 nM) during the exponentially growing phase, the cell survival rates were much lower. In combination with irradiation, SN-38 showed only additive effects to irradiation when cells were treated in confluent cultures. However, higher combination effects of SN-38 and irradiation were observed in the cells treated in the exponentially growing phase. When cells were irradiated during the exponentially growing phase, a significant combination effect of 200 nM SN-38 and irradiation was also observed in some cell lines, but not in others.


CONCLUSIONS
SN-38 and irradiation showed supraadditive effects in some cell lines, when treated in the exponentially growing phase, but not in other cell lines or when cells were treated in the confluent phase.
Sasai
K
K
Department of Radiology, Kyoto Univesity Hospital, Sakyo, Japan.
Guo
G Z
GZ
Shibuya
K
K
Oya
N
N
Shibata
T
T
Nagata
Y
Y
Hiraoka
M
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects / Q000528:radiation effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin