The significance of the sequence of administration of topotecan and etoposide.
OBJECTIVE
Often the best method of integrating chemotherapeutic agents is unknown. Recently there has been interest in the use of combinations of the topoisomerase II inhibitors and the topoisomerase I inhibitors as these agents have shown individual activity in malignancies such as non-small-cell lung cancer. This study examined the interaction of the topoisomerase II inhibitor etoposide with the topoisomerase I inhibitor topotecan (Tpt) in V79 cells (hamster lung fibroblast cells) to determine the optimal method of delivering these agents.


RESULTS
Cell survival was assessed by colony formation. Synergistic interactions were assessed by the median effect principle in which a combination index (CI) of less than one suggests a synergistic interaction. The V79 cells were exposed to sequential 24-h incubations with the two chemotherapeutic agents. Initially, equitoxic doses of the two agents were delivered (i.e. 0.0275 microg/ml of topotecan alone or 0.089 microg/ml of etoposide alone resulting in a surviving fraction of 70%; Tpt:etoposide ratio 1: 3.2). It was determined that a sequence-dependent synergistic interaction (CI < 1) resulted at a lower level of cytotoxicity if the etoposide exposure followed the Tpt exposure compared to the opposite sequence. This same effect was seen after treatment of cells with various concentration (microg/ml) ratios of Tpt: etoposide (1:4.0, 1:1, 2.5:1).


CONCLUSIONS
These results suggest that maximum synergy occurs for the delivery of etoposide following Tpt exposure (compared to the opposite sequence) and these findings may have important clinical implications.
Bonner
J A
JA
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Kozelsky
T F
TF
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005047:Etoposide / Q000008:administration & dosage*; D005347:Fibroblasts / Q000187:drug effects; D008168:Lung / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D005047:Etoposide; D019772:Topotecan; D002166:Camptothecin