Abstract
Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge.
Highlights
When investigating potential drugs for their clinical merit, the necessary experiments cannot and must not be performed with human patients directly
Several neuropharmacokinetic studies with patients suffering from brain tumours, which are summarized in a recent letter written by Stepanenko and Chekhonin, have shown that on average only 20% of systemic drug levels reach the brain
The Cancer Stem Cell (CSC) hypothesis proposes that tumours consist of hierarchically arranged populations of cells with CSCs being at the apex of the hierarchy–a subpopulation that has the ability to self-renew and to differentiate thereby recapitulating the entire functional diversity present within the original tumour [140]
Summary
When investigating potential drugs for their clinical merit, the necessary experiments cannot and must not be performed with human patients directly. As the precise nature of this drug’s effect on the cells might be still not fully understood, it is important to create the correct experimental context, as TMZ is an important component of complex combination therapies, such as the RIST (rapamycin, irinotecan, sunitinib, TMZ) protocol or the CUSP9 (coordinated undermining of survival paths with nine repurposed drugs) approach [20,21] In this context TMZ has been shown, even at low concentrations, to enhance the response of GB cells to radiation, or, in combination with a pharmacological PI3K/mTOR inhibitor, to break the increased apoptosis-resistance of certain GB cell populations [19,22]. We will discuss the experimental systems that have furthered our understanding of GB and TMZ and highlight the inherent and necessary limitations of these experiments that have led to gaps in our mechanistical understanding
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