Cancer Chemotherapy and Pharmacology

, Volume 55, Issue 4, pp 323–332

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

  • Yusuke Ochi
  • Yoshinobu Shiose
  • Hiroshi Kuga
  • Eiji Kumazawa
Original Article

DOI: 10.1007/s00280-004-0911-1

Cite this article as:
Ochi, Y., Shiose, Y., Kuga, H. et al. Cancer Chemother Pharmacol (2005) 55: 323. doi:10.1007/s00280-004-0911-1

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.

Keywords

DE-310Macromolecular prodrugDX-8951Cellular uptakeDrug releaseDrug delivery system

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Yusuke Ochi
    • 1
  • Yoshinobu Shiose
    • 1
  • Hiroshi Kuga
    • 1
  • Eiji Kumazawa
    • 1
  1. 1.New Product Research Laboratories IIIDaiichi Pharmaceutical Co., Ltd.TokyoJapan