title: A novel 2'-(N-methylpyridinium acetate) prodrug of paclitaxel induces superior antitumor responses in preclinical cancer models.
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.
authors.affiliation: Charité Children's Hospital, Humboldt University, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gaedicke
authors.forename: Rodney Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Johanne
authors.initials: J
authors.lastname: Renaud
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pitsinos
authors.forename: Kyriaco C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002417:Cattle; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009861:Onium Compounds; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009861:Onium Compounds; D011355:Prodrugs; D014404:Tubulin; D017239:Paclitaxel