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A possible mechanism for the long-lasting antitumor effect of the macromolecular conjugate DE-310: mediation by cellular uptake and drug release of its active camptothecin analog DX-8951

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Abstract

DE-310, a new macromolecular prodrug, was designed to enhance the pharmacological profiles of a novel camptothecin analog (DX-8951f), and a single treatment with DE-310 exhibits a similar or greater therapeutic effect than do optimally scheduled multiple administrations of DX-8951f in several types of tumors. In this study, the drug-release mechanism by which DE-310 excites antitumor activity was investigated in Meth A cells, a malignant ascites model of murine fibrosarcoma. A single i.v. injection of DE-310 at the maximum tolerated dose (MTD) prolonged survival of Meth A-bearing mice by 300%. DX-8951 and glycyl-8951 (G-DX-8951), enzymatic cleavage products of DE-310, were detected in serum and ascites fluid, and also in the culture medium of Meth A ascites cells incubated in vitro with DE-310. The total amounts of DX-8951, G-DX-8951, and conjugated DX-8951 in Meth A tumor cells were three times higher than that in macrophages. Furthermore, DX-8951-related fluorescence was observed in Meth A ascites cells obtained from Meth A-bearing mice that had received DE-310 or CM-Dex-PA-DX-8951 that does not release free DX-8951. DX-8951-related fluorescence was also observed at the site of lysosomes in cells incubated in vitro with DE-310 at 37°C, but not in those incubated at 4°C. Drugs were released from DE-310 by cysteine proteinase prepared from Meth A tumor tissue. These results suggest that the mechanism by which DX-8951 is released from DE-310 in vivo is involved in the process of uptake of DE-310 into tumor or macrophages, digestion by intracellular lysosomal cysteine proteinase, and subsequent secretion of the drugs.

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Acknowledgements

The authors wish to thank Mrs. M. Nakata for her excellent technical contribution and Dr. N. Tanaka and Dr. K. Inoue for their advice concerning this study.

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Authors and Affiliations

  1. New Product Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo, 134-8630, Japan

    Yusuke Ochi, Yoshinobu Shiose, Hiroshi Kuga & Eiji Kumazawa

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  1. Yusuke Ochi
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  2. Yoshinobu Shiose
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  3. Hiroshi Kuga
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  4. Eiji Kumazawa
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Correspondence to Yusuke Ochi.

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Ochi, Y., Shiose, Y., Kuga, H. et al. A possible mechanism for the long-lasting antitumor effect of the macromolecular conjugate DE-310: mediation by cellular uptake and drug release of its active camptothecin analog DX-8951. Cancer Chemother Pharmacol 55, 323–332 (2005). https://doi.org/10.1007/s00280-004-0911-1

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  • DOI: https://doi.org/10.1007/s00280-004-0911-1

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