Abstract

Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a “bystander effect”. In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using in silico spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling. The approach employs a number of experimental model systems to define parameters for the cellular uptake, metabolism and diffusion of both the prodrug and its metabolites. The model predicts rapid uptake of CP-506 to high intracellular concentrations with its long plasma half-life driving tissue diffusion to a penetration depth of 190 µm, deep within hypoxic activating regions. While bioreductive metabolism is restricted to regions of severe pathological hypoxia (<1 µM O2), its active metabolites show substantial bystander potential with release from the cell of origin into the extracellular space. Model predictions of bystander efficiency were validated using spheroid co-cultures, where the clonogenic killing of metabolically defective “target” cells increased with the proportion of metabolically competent “activator” cells. Our simulations predict a striking bystander efficiency at tissue-like densities with the bis-chloro-mustard amine metabolite (CP-506M-Cl2) identified as a major diffusible metabolite. Overall, this study shows that CP-506 has favourable pharmacological properties in tumour tissue and supports its ongoing development for use in the treatment of patients with advanced solid malignancies.

Highlights

  • IntroductionHeterogeneous tumour oxygenation has long been recognized as a major impediment to the development of effective cancer therapies (Hockel et al, 1996; Nordsmark et al, 2005; Wilson and Hay, 2011; Marusyk et al, 2012)

  • We investigate the extravascular transport properties and bystander efficiency of CP-506 in tumour tissues by coupling various experimental and computational modelling approaches

  • Clonogenic assays showed a similar trend with a 22-fold differential in anoxic sensitivity between the PORko-G and P450 oxidoreductase (POR)-R cell lines

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Summary

Introduction

Heterogeneous tumour oxygenation has long been recognized as a major impediment to the development of effective cancer therapies (Hockel et al, 1996; Nordsmark et al, 2005; Wilson and Hay, 2011; Marusyk et al, 2012). Given the prevalence of tumour hypoxia (Fukumura and Jain, 2007; Pries et al, 2009) and its association with treatment failure (Vaupel and Mayer, 2007), the use of hypoxia-activated prodrugs is a noteworthy approach to improve clinical outcomes. Hypoxia-activated prodrugs are designed to preferentially target regions of severe hypoxia, allowing tumour dose intensification by circumventing the normal tissue toxicities (Denny, 2005; Denny, 2010) that traditionally limit the potential for dose-escalation with conventional chemotherapeutic regimens (Rowinsky, 2000; Crawford, 2013). The prodrug must penetrate relatively long distances through the extravascular compartment in order to reach the cells that are sufficiently hypoxic for its metabolic activation and subsequent cytotoxicity. The localization of the hypoxic target cells and the relative degree of effector redistribution (known as the bystander effect) determine the resultant cell killing. The limited success of earlier clinical candidates reflects, in part, the complexity of this design criteria (Marcu and Olver, 2006; Spiegelberg et al, 2019; Li et al, 2021)

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