Prodrug Strategies for Targeting Tumour Hypoxia

Wilson, William R.; Hicks, Kevin O.; Wang, Jingli; Pruijn, Frederik B.

doi:10.1007/978-1-4614-9167-5_13

Cited by 2 publications

(2 citation statements)

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“…One of the attractive features of prodrugs that are activated within tumors is their potential for decoupling targeting and pharmacodynamic effect through diffusion of active metabolites from prodrug-activating cells to surrounding untargeted cells. These bystander effects are thought to be important for monotherapy activity of targeted anticancer prodrugs (2–4), including hypoxia-activated prodrugs (HAP) activated by bioreduction in hypoxic regions (5–7). Bystander effects may also be important for activity of HAP in combination with agents that spare hypoxic cells, such as ionizing radiation; activation of most HAP is inhibited by O 2 concentrations too low to effect radiosensitization (8–11), so there is likely a subpopulation of radioresistant hypoxic cells that can only be killed by HAP if bystander metabolites diffuse from severely hypoxic regions (5).…”

Section: Introductionmentioning

confidence: 99%

“…PR-104 was chosen because its mechanism of action is well understood (7), its active metabolites are known to be capable of diffusing from cells (13) and thus are expected to elicit a bystander effect, and validated analytical methods for their quantitation are available (14). The phosphate ester moiety of PR-104 is rapidly converted systemically to the corresponding alcohol PR-104A (13, 15), which is a prodrug that is activated by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) and amine (PR-104M), both of which are DNA crosslinking cytotoxins (16, 17).…”

Section: Introductionmentioning

confidence: 99%

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The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

Foehrenbacher¹,

Patel²,

Abbattista³

et al. 2013

Front. Oncol.

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Activation of prodrugs in tumors (e.g., by bioreduction in hypoxic zones) has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such “bystander effects” may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of bystander effects to antitumor activity for the first time, by developing a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model for PR-104, a phosphate ester pre-prodrug that is converted systemically to the hypoxia-activated prodrug PR-104A. Using Green’s function methods we calculated concentrations of oxygen, PR-104A and its active metabolites, and resultant cell killing, at each point of a mapped three-dimensional tumor microregion. Model parameters were determined in vitro, using single cell suspensions to determine relationships between PR-104A metabolism and clonogenic cell killing, and multicellular layer (MCL) cultures to measure tissue diffusion coefficients. LC-MS/MS detection of active metabolites in the extracellular medium following exposure of anoxic single cell suspensions and MCLs to PR-104A confirmed that metabolites can diffuse out of cells and through a tissue-like environment. The SR-PK/PD model estimated that bystander effects contribute 30 and 50% of PR-104 activity in SiHa and HCT116 tumors, respectively. Testing the model by modulating PR-104A-activating reductases and hypoxia in tumor xenografts showed overall clonogenic killing broadly consistent with model predictions. Overall, our data suggest that bystander effects are important in PR-104 antitumor activity, although their reach may be limited by macroregional heterogeneity in hypoxia and reductase expression in tumors. The reported computational and experimental techniques are broadly applicable to all targeted anticancer prodrugs and could be used to identify strategies for rational prodrug optimization.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

Foehrenbacher¹,

Patel²,

Abbattista³

et al. 2013

Front. Oncol.

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Design of Optimized Hypoxia-Activated Prodrugs Using Pharmacokinetic/Pharmacodynamic Modeling

et al. 2013

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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.

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Prodrug Strategies for Targeting Tumour Hypoxia

Cited by 2 publications

References 243 publications

The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

Design of Optimized Hypoxia-Activated Prodrugs Using Pharmacokinetic/Pharmacodynamic Modeling

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