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Publications à Abstracts |
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Development of a novel prodrug of paclitaxel that is cleaved by
prostate-specific antigen: an in vitro and in vivo evaluation study Bakheet Elsadek, Ralph Graeser, Norbert
Esser, Cynthia Schäfer-Obodozie,
Khalid
Abu Ajaj, Clemens Unger, André Warnecke,
Tahia Saleem, Nagla El-Melegy, Hafez Madkor, Felix Kratz European Journal of Cancer, 2010, 46 (18), 3434–3444 Keywords: paclitaxel; prodrug; human serum albumin;
prostate-specific antigen; orthotopic animal model,
in vivo bioluminescence; prostate cancer. Abstract: In developed countries, prostate cancer is the third most common cause
of death from cancer in men. Unfortunately, while accumulating clinical data
have suggested that taxanes may prolong the
survival in a subset of men with prostate carcinoma, the dose and duration of
administration of these drugs are limited by their significant systemic
toxicities due to a lack of tumor selectivity. In an attempt to improve both
the water solubility and tumor targeting properties of paclitaxel (Taxol®), we set out to develop a water soluble
paclitaxel prodrug that is activated specifically by prostate-specific
antigen (PSA) which is almost exclusively expressed in prostate tissue and
prostate carcinoma making it an ideal molecular target for prodrugs strategies.
Using albumin as drug carrier, we describe a novel albumin-binding prodrug of
paclitaxel, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Leu-PABC-paclitaxel
[EMC: ε-maleimidocaproyl; PABC: p-aminobenzyloxycarbonyl]
that was synthesized by reacting EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-OH
with H-Leu-PABC-paclitaxel. This prodrug was water
soluble and was bound to endogenous and exogenous albumin. Moreover,
incubation studies with PSA demonstrated that the albumin-bound form of the
prodrug was cleaved rapidly at the P1–P1' scissile bond releasing the
paclitaxel dipeptide H-Ser-Leu-PABC-paclitaxel.
Last but not least, due to the incorporation of a PABC self-eliminating
linker, this dipeptide was rapidly degraded to
liberate paclitaxel as a final cleavage product within a few hours in
prostate tumor tissue homogenates. Of note was that the albumin-bound form of
the prodrug was approximately three-fold more active in killing PSA-positive LNCaP cells than paclitaxel. In addition, orientating
toxicity studies in mice showed that the maximum tolerated dose of the novel
paclitaxel prodrug was twice that of conventional paclitaxel. When tested in vivo in an orthotopic
mouse model of human prostate cancer using luciferase-transduced
LNCaP LLN cells, both paclitaxel and the new
paclitaxel prodrug showed distinct antitumor efficacy on the primary tumor
and metastases that was significantly better than the effect of doxorubicin
that was used as a comparison and showed no antitumor efficacy. The new
paclitaxel prodrug (3 × 24 mg paclitaxel equivalents) showed comparable
antitumor activity on the primary tumor to paclitaxel at its maximum
tolerated dose (3 × 12 mg/kg), redciced circulating
PSA levels and demonstrated a better antitumour effect on lung metastases but not on bone
metastases. |
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