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

• Published in: International journal of cancer Vol. 50; no. 5; p. 760
• Main Authors: Kim, R, Hirabayashi, N, Nishiyama, M, Jinushi, K, Toge, T, Okada, K
• Format: Journal Article
• Language: English
• Published: United States 12.03.1992
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Camptothecin - therapeutic use; DNA Topoisomerases, Type I - analysis; DNA Topoisomerases, Type II - analysis; DNA Topoisomerases, Type II - genetics; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Humans; Irinotecan; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - enzymology; Topoisomerase II Inhibitors; Transplantation, Heterologous
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910500516

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.