Paclitaxel-2′-Ethylcarbonate Prodrug Can Circumvent P-glycoprotein-mediated Cellular Efflux to Increase Drug Cytotoxicity

@article{Tanino2006Paclitaxel2EthylcarbonatePC,
  title={Paclitaxel-2′-Ethylcarbonate Prodrug Can Circumvent P-glycoprotein-mediated Cellular Efflux to Increase Drug Cytotoxicity},
  author={Tadatoshi Tanino and Akihiro Nawa and Eisaku Kondo and Fumitaka Kikkawa and Tohru Daikoku and Tatsuya Tsurumi and Chenhong Luo and Yukihiro Nishiyama and Yuki Takayanagi and Katuhiko Nishimori and Seiji Ichida and Tetsuyuki Wada and Yasuyoshi Miki and Masahiro Iwaki},
  journal={Pharmaceutical Research},
  year={2006},
  volume={24},
  pages={555-565}
}
PurposeThe aim of the study was to investigate whether 2′-ethylcarbonate-linked paclitaxel (TAX-2′-Et) circumvents P-glycoprotein (P-gp)-mediated cellular efflux and cytotoxicity enhanced by TAX-2′-Et activation within human culture cells transfected with a rabbit liver carboxylesterase (Ra-CES) cDNA.Materials and MethodsTAX-2′-Et transport was characterized in a human colon carcinoma cell line (Caco-2) and paclitaxel (TAX)-resistant ovarian carcinoma cells (SKOV3/TAX60). Expression of P-gp… 
Enzymatic stability of 2′‐ethylcarbonate‐linked paclitaxel in serum and conversion to paclitaxel by rabbit liver carboxylesterase for use in prodrug/enzyme therapy
TLDR
The results indicate that TAX‐2′‐Et is sensitive to serum CESs, but not cholinesterases, however, serum CESS show species‐dependent hydrolysis of TAX •2‐ethylcarbonate‐linked paclitaxel, which may be beneficial for the development of a TAX-2‐2-Et/enzyme therapy strategy for ovarian cancer.
Approaches to minimize the effects of P-glycoprotein in drug transport: A review.
TLDR
Estimation strategies, one of the most important approaches to mimic the P-gp transporter's action, finally enhancing the oral bioavailability of the drug by inhibiting its P-GP efflux and a prodrug approach might be a useful strategy to overcome drug resistance.
Organic anion transporting polypeptide 2‐mediated uptake of paclitaxel and 2′‐ethylcarbonate‐linked paclitaxel in freshly isolated rat hepatocytes
TLDR
The hepatic uptake of paclitaxel and its P‐gp‐insensitive prodrug, 2′‐ethylcarbonate‐linked pac litaxel (TAX‐2′‐Et), has been characterized using freshly isolated and pregnenolone‐16‐α‐carbonitrile (PCN)‐treated hepatocytes in rats.
The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs
TLDR
Cell proliferation assays in ductal pancreatic cancer cells indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs and enhanced potency of nucleoside analogs was attributed to their improved membrane permeability.
Targeted chemotherapy in drug-resistant tumors, noninvasive imaging of P-glycoprotein-mediated functional transport in cancer, and emerging role of Pgp in neurodegenerative diseases.
TLDR
This tutorial makes an attempt in outlining strategies capable of delivering chemotherapeutic agents into drug-resistant tumors and targeted radiopharmaceuticals acting as ultrasensitive molecular imaging probes for detecting functional Pgp expression in vivo to assist management of drug resistance in cancer and treatment of neurodegenerative diseases.
Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles.
TLDR
The current review provides a summary of the mechanisms by which lipophilic conjugates, including in combination with delivery vehicles, can be used to control drug delivery, distribution and therapeutic profiles, to provide a toolbox to assist researchers to design and optimise drug candidates.
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