Tumor Physiology and Charge Dynamics of Anticancer Drugs: Implications for Camptothecin-based Drug Development

Author(s): D. J. Adams, L. R. Morgan

Journal Name: Current Medicinal Chemistry

Volume 18 , Issue 9 , 2011


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Abstract:

Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa's and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development.

Keywords: Camptothecin, charge dynamics, glycolytic phenotype, hypoxia, pKa, topoisomerase I, tumor pH gradient, Anticancer, ionization, receptor

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Article Details

VOLUME: 18
ISSUE: 9
Year: 2011
Page: [1367 - 1372]
Pages: 6
DOI: 10.2174/092986711795029609
Price: $65

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