Skip to Main content Skip to Navigation
Theses

Conception, synthèse et évaluations biologiques de prodrogues du paclitaxel et du docetaxel activées par voie enzymatique dans le cadre des stratégies de chimiothérapie anticancéreuse ADEPT et PMT

Abstract : Paclitaxel (Taxol®), and its semisynthetic analog docetaxel (Taxotere®), belong to a family of antitumoral agents whose original features include an inusual tetracyclic core and an innovative mechanism of action. Indeed, they target tubulin, a protein of the mitotic spindle.
Though they are widely used in clinic (breast, ovary and lung cancers), yet they display a major drawback : their acute toxicity and way of administration induct severe side-effects. Also, some problems of drug resistance appear as well.
An efficient way of improving these compounds is to transform them in less cytotoxic more hydrophilic prodrugs. This allows a more target-directed delivery, more specific for tumors. These prodrugs could be then used in such strategies as PMT (Prodrug Mono Therapy) or an immuno-targeted one like ADEPT (Antibody Directed Enzyme Prodrug Therapy).

To this end, glucuronated prodrugs of paclitaxel and docetaxel have been designed and synthesized. The spacer used is a double one, connecting a p-hydroxybenzyl carbamate with a diamine tether. In order to validate this approach, these prodrugs have been biologicaly evaluated (stabilities, cytotoxicities, enzymatic hydrolyses). The double spacer showed good results, especially efficient release of the drug from the prodrug when incubated with the proper enzyme. Compared to former spacers used, it showed improved properties. The design and synthesis of other spacers suitable for the preparation of such prodrugs are also described.
Complete list of metadatas

https://tel.archives-ouvertes.fr/tel-00009862
Contributor : Emmanuel Bouvier <>
Submitted on : Tuesday, September 6, 2005 - 6:52:47 PM
Last modification on : Tuesday, July 21, 2020 - 3:58:22 AM
Long-term archiving on: : Friday, September 14, 2012 - 2:05:37 PM

Identifiers

  • HAL Id : tel-00009862, version 1

Collections

Citation

Emmanuel Bouvier. Conception, synthèse et évaluations biologiques de prodrogues du paclitaxel et du docetaxel activées par voie enzymatique dans le cadre des stratégies de chimiothérapie anticancéreuse ADEPT et PMT. Médicaments. Université René Descartes - Paris V, 2003. Français. ⟨tel-00009862⟩

Share

Metrics

Record views

746

Files downloads

6013