Abstract
Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP). HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000), are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302) are maximally activated only under extreme hypoxia, but their active metabolites (effectors) diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug, and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervessel distances (based on a cremaster muscle microvessel network) was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic.
Highlights
Prodrugs that are enzymatically converted to active metabolites within tumors are of interest for selective cancer therapy
In order to identify optimal properties of Hypoxia-activated prodrugs (HAP), we developed a SR-pharmacokinetic/ pharmacodynamic (PK/PD) model that captures the key features of both Class I and Class II HAP (Figure 2)
TISSUE MICROREGIONS USED FOR SR-PK/PD MODELING We used a digitized 3D tumor microregion (Figure 3A) that was derived by mapping a region of a subcutaneous FaDu tumor xenograft grown in a mouse dorsal window chamber [57]
Summary
Prodrugs that are enzymatically converted to active metabolites (effectors) within tumors are of interest for selective cancer therapy. In the present study we utilize pharmacokinetic/ pharmacodynamic (PK/PD) models to explore relationships between the reaction/diffusion properties of HAP in the tumor microenvironment and their antitumor activity and selectivity. In this context it is useful to distinguish two broad classes of HAP with different PK/PD features (Figure 1). Class I HAP are activated by reduction under relatively mild hypoxia to generate a reactive cytotoxin, which is restricted to the cell in which it is formed. In the case of PR-104A, a KO2 value of ~0.1 μM has been estimated in stirred single cell suspensions [31], www.frontiersin.org
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