Abstract
Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.
Highlights
Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive childhood malignancy of the brainstem with a 2-year survival rate of 10% [1, 2]
We aim to review all chemotherapeutic drugs administered systemically to diffuse intrinsic pontine glioma (DIPG) patients by means of a theoretical model including all physicochemical properties that influence passive diffusion, to indicate their likeliness of passage over an intact bloodbrain barrier (BBB) in DIPG
We aim to indicate whether local administration of these drugs via convection-enhanced delivery (CED) may increase their therapeutic potential
Summary
Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive childhood malignancy of the brainstem with a 2-year survival rate of 10% [1, 2]. Unlike the spectacular increase in survival of childhood leukemia patients from
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