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[Cancer Research 51, 4187-4191, August 15, 1991]
© 1991 American Association for Cancer Research
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Intracellular Roles of SN-38, a Metabolite of the Camptothecin Derivative CPT-11, in the Antitumor Effect of CPT-11

Yasuyoshi Kawato1, Masashi Aonuma, Yasuhide Hirota, Hiroshi Kuga and Keiki Sato

Exploratory Research Laboratories 1, Daiichi Pharmaceutical Co., Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134, Japan

It is known that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a semisynthesized derivative of camptothecin (CPT), has a potent antitumor activity in vivo, but 7-ethyl-10-hydroxycamptothecin (SN-38), a metabolite of CPT-11, shows much stronger cytotoxicity in vitro than CPT-11. In this study, we demonstrated that the relaxation of SV40 DNA plasmids by type I DNA topoisomerase prepared from P388 murine leukemia cells was inhibited by 50% by SN-38 at approximately 1 µM, although CPT-11 at 1 mM slightly inhibited the relaxation. SN-38 and CPT showed strong, time-dependent inhibitory activity against DNA synthesis of P388 cells. However, CPT-11 weakly inhibited DNA synthesis independently of time with coincident inhibition of the total thymidine uptake by the cells. By alkaline and neutral elution assays, it was demonstrated that SN-38 caused much more frequent DNA single-strand breaks in P388 cells than did CPT-11. The same content of SN-38 and a similar frequency of single-strand breaks were detected in the cells treated with SN-38 at 0.1 µM or with CPT-11 at 100 µM. Therefore, single-strand breaks by CPT-11 seem to be due to SN-38 produced from CPT-11 in cells. These results indicate that CPT-11 itself possesses a marginal antiproliferative effect but that SN-38 plays an essential role in the mechanism of action of CPT-11.

1 To whom requests for reprints should be addressed.

Received 1/10/91. Accepted 6/ 4/91.




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C. J. van Groeningen, W. J. F. Van der Vijgh, J. J. Baars, H. Stieltjes, K. Huibregtse, and H. M. Pinedo
Altered Pharmacokinetics and Metabolism of CPT-11 in Liver Dysfunction: A Need for Guidelines
Clin. Cancer Res., April 1, 2000; 6(4): 1342 - 1346.
[Abstract] [Full Text]

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R. Humerickhouse, K. Lohrbach, L. Li, W. F. Bosron, and M. E. Dolan
Characterization of CPT-11 Hydrolysis by Human Liver Carboxylesterase Isoforms hCE-1 and hCE-2
Cancer Res., March 1, 2000; 60(5): 1189 - 1192.
[Abstract]