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

Wolfgang Wrasidlo, Gerhard Gaedicke, Rodney Kiplin Guy, Johanne Renaud, Emmanuel Pitsinos, Kyriaco C. Nicolaou, Ralph A. Reisfeld, Holger N. Lode

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish
Pages (from-to)1093-1099
Number of pages7
JournalBioconjugate Chemistry
Issue number5
StatePublished - 2002

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry


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