Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice.
Topoisomerase (topo) I and II are nuclear enzymes which are novel targets of cancer chemotherapy. A new camptothecin (CPT) analog, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyl-oxy-CPT (CPT-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 1 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-11 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.
Kim
R
R
Department of Surgery, Hiroshima University, Japan.
Hirabayashi
N
N
Nishiyama
M
M
Jinushi
K
K
Toge
T
T
Okada
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000032:analysis*; D004250:DNA Topoisomerases, Type II / Q000032:analysis* / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D000077146:Irinotecan; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin