TY - JOUR
T1 - A novel 2′-(N-methylpyridinium acetate) prodrug of paclitaxel induces superior antitumor responses in preclinical cancer models
AU - Wrasidlo, Wolfgang
AU - Gaedicke, Gerhard
AU - Guy, Rodney Kiplin
AU - Renaud, Johanne
AU - Pitsinos, Emmanuel
AU - Nicolaou, Kyriaco C.
AU - Reisfeld, Ralph A.
AU - Lode, Holger N.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
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U2 - 10.1021/bc0200226
DO - 10.1021/bc0200226
M3 - Article
C2 - 12236791
AN - SCOPUS:0036740121
SN - 1043-1802
VL - 13
SP - 1093
EP - 1099
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 5
ER -