Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6- guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 146 months Treatment failure has been associated with the tumor drug resistance This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use

Temozolomide: An Updated Overview of Resistance Mechanisms, Nanotechnology Advances and Clinical Applications.

Anticancer activity of flavonoids isolated from Achyrocline satureioides in gliomas cell lines.

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.

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Considering the Experimental use of Temozolomide in Glioblastoma Research

We designed a conjugated compound by coupling temozolomide (TMZ) with doxorubicin (DOX) via an acylhydrazone linkage as a potential prodrug used for glioblastoma multiforme (GBM) treatment. Viscosity and spectroscopic studies revealed that the drug conjugate could act as a nonclassical double intercalating agent. Although free TMZ is an inefficient DNA binder in comparison to DOX, the TMZ moiety interacted with DNA as an induced intercalator, arising from the synergistic effect of DOX moiety that mediated conformational changes of the DNA helix. Two binding modes were proposed to interpret the double intercalating effect of the drug conjugate on intra- and inter-DNA interactions that could cause DNA cross-linking and fibril aggregates. We also developed a delivery nanoplatform with a loading efficiency of 83% using copper-bound apoferritin as a nanocarrier. In sharp contrast to the short half-life of free TMZ, the nanocomposite was stable under physiological conditions without detectable drug decomposition after a 2 week storage, and drug release was activatable in the presence of glutathione at millimolar levels. The antitumor effect of the drug conjugate and nanocomposite against GBM cells was reported to demonstrate the potential therapeutic applications of double intercalating materials.

Temozolomide-Doxorubicin Conjugate as a Double Intercalating Agent and Delivery by Apoferritin for Glioblastoma Chemotherapy.

Efficient delivery of Temozolomide using ultrasmall large-pore silica nanoparticles for glioblastoma.

Temozolomide analogs with improved brain/plasma ratios - Exploring the possibility of enhancing the therapeutic index of temozolomide.

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Temozolomide analogs with improved brain/plasma ratios - Exploring the possibility of enhancing the therapeutic index of temozolomide.