Sensor/effector drug design with potential relevance to cancer.
Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their 'healthy' counterparts. Some tumors, such as solid lung carcinoma, are hypoxic, and its cells are therefore more reducing than normal, while others, such as the ones of breast and prostate cancer, proliferate under oxidative stress (OS). These biochemical differences between normal and tumor tissue are significant, and can be used to design effective, yet selective redox drugs. The resulting drug design can follow different avenues. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro-drug molecules inside cancer cells by a reductive step, often followed by further chemical transformations, such as hydrolysis. Related anti-cancer compounds, such as varacin, employ an intricate combination of reduction and oxidation processes to develop their therapeutic potential inside cells. Another, just emerging approach considers the use of pro-oxidants and catalysts, taking advantage of the inherent efficiency and selectivity associated with OS-induced cell death. Even more complex tactics, such as chelator-assisted photodynamic therapy, exploit the intracellular metal homeostasis to target cancer cells. Together, all of these avenues try to endow molecules with a combination of sensor and effector properties, which might allow them to single out and selectively kill cancer cells without the need for cell-selective drug delivery systems. In the long term, such agents could be associated with high efficiency, good selectivity and dramatically reduced drug side effects.
Fry
Fiona H
FH
School of Biosciences, University of Exeter, Stocker Road, Exeter EX4 4QD, United Kingdom.
Jacob
Claus
C
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism; D002384:Catalysis; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010778:Photochemotherapy; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D016877:Oxidants; D011355:Prodrugs; D017382:Reactive Oxygen Species; D013440:Sulfides