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A novel 2 '-(n-methylpyridinium acetate) prodrug of paclitaxel induces superior antitumor responses in preclinical cancer models

Academic Article
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Overview

related to degree

  • Guy, Rodney Kiplin, Ph.D. in Chemistry, Scripps Research 1991 - 1996

authors

  • Wrasidlo, W.
  • Gaedicke, G.
  • Guy, Rodney Kiplin
  • Renaud, J.
  • Pitsinos, E.
  • Nicolaou, K.C.
  • Reisfeld, Ralph
  • Lode, H. N.

publication date

  • 2002

journal

  • Bioconjugate Chemistry  Journal

abstract

  • The development of novel strategies for the treatment of malignancies by successful intervention in advanced stage disease is a major challenge in oncology. We tested the hypothesis that this can be achieved by the rational design of taxoid onium salts modified at C-7 and C-2' positions. The characterization of these molecules revealed a dramatically improved water solubility and prodrug behavior in plasma. Specifically, all compounds released parental paclitaxel with half-lives ranging from 0.9 to 180 min. In the absence of plasma, only the 2'-(N-methylpyridinium acetate) derivative of paclitaxel (2'-MPA-paclitaxel) revealed a complete abrogation of paclitaxel specific microtubule assembly disassembly dynamics and a 3 log reduction in cellular binding, indicating that reversible blockage of the C-2' position by methylpyridinium acetate yields a true paclitaxel prodrug. Structure/activity profiles of all compounds in tissue culture revealed cytotoxicity effective at picomolar concentrations with a panel of 16 cancer cell lines in contrast to 4 nonmalignant cell lines. Importantly, the decisive cytotoxic potential observed in vitro for all compounds correlated only with in vivo findings for 2'-MPA-paclitaxel. Specifically, the 2'-MPA-paclitaxel prodrug induced regression of primary tumors in three xenograft models of nonsmall cell lung carcinoma, ovarian carcinoma and prostate cancer, in contrast to ineffective C-7 derivatives and parental paclitaxel. At the same time, a reduced systemic toxicity of 2'-MPA-paclitaxel was observed in contrast to a far more toxic parental paclitaxel. Taken together, these findings demonstrate that the 2'-MPA-paclitaxel prodrug is a promising new candidate for cancer therapy.

subject areas

  • Animals
  • Antineoplastic Agents
  • Cattle
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms, Experimental
  • Onium Compounds
  • Paclitaxel
  • Prodrugs
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Treatment Outcome
  • Tubulin
  • Tumor Cells, Cultured
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Identity

International Standard Serial Number (ISSN)

  • 1043-1802

Digital Object Identifier (DOI)

  • 10.1021/bc0200226

PubMed ID

  • 12236791
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Additional Document Info

start page

  • 1093

end page

  • 1099

volume

  • 13

issue

  • 5

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