Topoisomerase (topo) I and II are nuclear enzymes which are novel targets of cancer chemotherapy. A new camptothecin (CPT) analog, 7-ethyl-I0-[4-( I -piperidino)-I -piperidino]carbonyl-oxy-CPT (CPT-I I). is a topo-l inhibitor with a higher activity and less toxicity than CPT. To investigate topo-l and -11-targeting chemotherapy in an in vivo model, we studied the effect of sequential or co-treatment using CPT-I I and adriamycin (ADR) a topo-ll inhibitor, in 6 human tumor xenografts (2 esophageal, 2 gastric and 2 colon tumor lines). In sequential treatment, adriamycin was administered i.v. 24 hr after CPT-II treatment, and no antagonistic effect of this treatment schedule was observed. ADR cytotoxicity was potentiated significantly by CPT-I I pretreatment in the case of 2 esophageal and 2 gastric tumor lines and I colon tumor line. On the other hand, co-treatment abolished the sensitivity to CPT-I I and ADR in all 6 tumor lines. Moreover, CPT-I I did not significantly enhance the cytotoxicity of other agents tested, including mitomycin C (MMC) and cisplatin (CDDP). Flow cytometry and dot-blot analyses showed that CPT-I I pretreatment induced an increase in the S-phase cell population with an increase of topo-ll mRNA expression after 24 and 48 hr, respectively, in the esophageal and colon tumor lines. These results suggest that CPT-I I can modulate topo-ll levels to enhance the effect of topo-ll inhibitors in some human tumors, and this suggests a new clinical method of topo-l and -11 targeting chemotherapy for human solid tumors.
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