Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice

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Abstract
Topoisomerase (topo) I and II are nuclear enzymes which are novel targets of cancer chemotherapy. A new camptothecin (CRT) analog, 7‐ethyl‐10‐[4‐(I‐piperidino)‐I‐piperidino]carbonyl‐oxy‐CPT (CRT‐11), is a topo‐I inhibitor with a higher activity and less toxicity than CPT. To investigate topo‐I and‐II‐targeting chemotherapy in an in vivo model, we studied the effect of sequential or co‐treatment using CPT‐11 and adriamycin (ADR) a topo‐II 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‐11 treatment, and no antagonistic effect of this treatment schedule was observed. ADR cytotoxicity was potentiated significantly by CPT‐11 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‐11 and ADR in all 6 tumor lines. Moreover, CPT‐11 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‐11 pretreatment induced an increase in the S‐phase cell population with an increase of topo‐II mRNA expression after 24 and 48 hr, respectively, in the esophageal and colon tumor lines. These results suggest that CPT‐11 can modulate topo‐II levels to enhance the effect of topo‐II inhibitors in some human tumors, and this suggests a new clinical method of topo‐I and‐II targeting chemotherapy for human solid tumors.