We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Design and Mechanism of Action of a New Prototype of Combi-Molecule "Programed" to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment.
- Authors
Larroque-Lombard, Anne-Laure; Chatelut, Etienne; Delord, Jean-Pierre; Imbs, Diane-Charlotte; Rochaix, Philippe; Jean-Claude, Bertrand; Allal, Ben; Frija, Luís M. T.
- Abstract
The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a "combi-molecule" to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model. Its target modulation was studied by western blotting and immunohistochemistry. AL530 released PD98059+CBL-A at mild acidic pH and in vitro was fivefold more potent than CBL and three-to-fivefold more potent than CBL+PD98059. In vivo it released high levels of PD98059 in tumors with a tumor/plasma ratio of five. It induced γ-H2AX phosphorylation and blocked pErk1,2, indirectly indicating its ability to damage DNA and modulate MEK. It induced significant tumor delay and less toxicity at unachievable doses for CBL and CBL+PD98059. We demonstrated the feasibility of a pH-labile combi-molecule capable of delivering high MEK inhibitor concentration in tumors, damaging DNA therein, and inducing tumor growth delay.
- Subjects
TUMOR microenvironment; DNA damage; ALKYLATING agents; TUMOR growth; WESTERN immunoblotting
- Publication
Pharmaceuticals (14248247), 2021, Vol 14, Issue 2, p160
- ISSN
1424-8247
- Publication type
Article
- DOI
10.3390/ph14020160