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.
Highlights
In advanced stages, the clinical management of solid tumors is primarily based on the combination of potent cytotoxic agents
We proposed an alternative approach that consists of designing type I combi-molecules to be hydrolyzed under tumor “microenvironment” conditions
AL530 was capable of inhibiting mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) and its Erk1,2 substrates in cells, we examined its effect on the phosphorylation status of MEK
Summary
The clinical management of solid tumors is primarily based on the combination of potent cytotoxic agents. In order to improve the therapeutic index, efforts are directed at combinations of cytotoxic agents with targeted therapy. The fundamental premise of the approach was to bring together multiple mechanisms of action in a single molecule, thereby reducing the pharmacotoxicology associated with multiple drug-related mechanisms to that of a single agent. This approach will reduce the incidence of additive toxicity associated with classical combinations. Three types of combi-molecules (type I, II and III) emerged [8]
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