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Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
Alternative schedules of TMZ in combination with topotecan or irinotecan may be a reasonable option in patients with high-grade CNS tumors as well as sarcomas and neuroblastomas with recurrence after standard therapy.70–73 The role of lower-dose, dose-dense, or metronomic regimens with or without drug combination and the role of TMZ for newly diagnosed low-grade glioma still have to be determined. It has been demonstrated that the promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) in primary or recurrent glioblastoma is a strong prognostic factor in adult patients treated with primary TMZ or rechallenged with TMZ at relapse. Strategies to overcome MGMT-mediated resistance, for example by depletion of MGMT by prolonged exposure to low doses of TMZ or other alkylating agents, by dose intensification of TMZ or addition of MGMT inhibitors such as O6-benzylguanine, are currently under evaluation.74–76
Precision medicine for brain gliomas
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Johnston et al. (2013) developed a patient-specific mathematical model for glioblastoma, yet the incidence is low, posing difficulty in creating statistically powered clinical trials, delaying advances in treatment. This model for disease progression coupled with clinical imaging data may provide a tool for quantifying each individual tumor's response relative to its inherent growth kinetics rather than a universal approach, and, potentially, predicting treatment efficacy. They used this model to evaluate therapeutic effect of a novel treatment for newly diagnosed glioblastoma compared to standard care treatment. Patient-specific mathematical modeling can be used to evaluate treatment gains in small clinical-trial design. The addition of O6-benzylguanine to temozolomide in the postradiotherapy milieu can provide greater treatment gains per milligram of temozolomide dose than temozolomide alone (Adair et al., 2014).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Strategies to overcome ATase-mediated resistance include divided dose scheduling, and/or co-administration of an ATase inhibitor, the prototype of which is O6-benzylguanine (Figure 5.5). Structure activity studies have shown that replacing the benzene ring of the O6-benzyl substituent with more polar unsubstituted or substituted heterocyclic rings can lead to a better fit within the enzyme’s active site and greater inhibitory activity. Thus, the bromothiophene analog lomeguatrib (“Patrin” or “PaTrin-2”) emerged as one of the most potent ATase inhibitors of this class with a good toxicity profile (Figure 5.5). However, in a clinical trial reported in 2008, a combination of lomeguatrib and temozolomide was not more efficacious in patients with metastatic colorectal cancer compared to temozolomide alone. This was despite in vitro pharmacodynamic studies in peripheral blood mononuclear cells (PBMC) demonstrating consistent depletion of O6-methylguanine-DNA methyltransferase at concentration levels of lomeguatrib comparable to those observed in the plasma of patients in the clinical trial. Structures of the O6-alkyl-DNA alkyltranferase (ATase) inhibitors O6-benzylguanine and PatrinTM.
Biodegradable hybrid-structured nanofibrous membrane supported chemoprotective gene therapy enhances chemotherapy tolerance and efficacy in malignant glioma rats
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Shih-Jung Liu, Tao-Chieh Yang, Shun-Tai Yang, Ying-Chun Chen, Yuan-Yun Tseng
Malignant glioma (MG) is one of the most common and treatment-resistant human tumours, with a median overall survival of 12–14 months [1,2]. Chemotherapy, radiotherapy and surgical excision are core components of the management of MG. The current standard treatment for patients with MG aged younger than 70 years is maximal surgical debulking followed by standard radiotherapy with concomitant and adjuvant chemotherapy with temozolomide (TMZ) [3,4]. The only two chemotherapeutics approved by the US Food and Drug Administration (FDA) for the treatment of MG, TMZ and carmustine (BCNU), both exert their therapeutic effect through alkylation [5]. Unfortunately, the majority of patients with MG treated with alkylators demonstrate de novo or acquired resistance with subsequent tumour progression [5]. The major cause of resistance to alkylating agents, such as BCNU and TMZ is O6-alkylguanine-DNA alkyltransferase (AGT), which is a DNA repair protein that removes and repairs O6-alkylguanine lesions initiated by alkylating agents [6]. O6-benzylguanine (O6-BG) is an AGT substrate that inactivates AGT and enhances the cytotoxicity of alkylators both in vitro and in vivo [6,7].
Drug clearance by aldehyde oxidase: can we avoid clinical failure?
Published in Xenobiotica, 2022
Francesca Toselli, Melanie Golding, Johan Nicolaï, Eric Gillent, Hugues Chanteux
Our IVIVC model was then validated in two ways: firstly, all compounds were qualitatively analysed for metabolite formation by UPLC-QTOF-MS, in parallel to parent depletion by UPLC-MS/MS. All compounds, including those with low or unmeasurable CLint and/or CLint,vitro,AO, formed at least one oxidation product inhibited by hydralazine, indicating AO metabolism; by contrast, the formation of other products, likely from P450-mediated metabolism, was not inhibited (data not shown). The same oxidative metabolites, however, may be formed by multiple enzymes, including P450s. With the exception of O6-benzylguanine however, none of these compounds are known to be metabolised by isoforms inhibited by hydralazine (CYP1A2, CYP2C8 and CYP2D6; Figure 1 and Table 6). Overestimation of their CLbAO due to P450 inhibition seems therefore unlikely. Contribution of CYP1A2 to the oxidation of O6-benzylguanine to 8-oxo-O6-benzylguanine has been suggested (Roy et al. 1995). Knowing that hydralazine can also inhibit CYP1A2, we assessed in separate experiments whether the CLbAO of this compound could have been overestimated due to cross-inhibition of this enzyme. As expected, O6-benzylguanine was metabolised to a single product, identified as 8-oxo-O6-benzylguanine by co-elution with an authentic standard. The formation of this metabolite or parent depletion, however, was not affected by furafylline, a potent and selective time-dependent CYP1A2 inhibitor (data not shown), confirming AO as the only enzyme responsible for O6-benzylguanine metabolism, in line with other findings (Strelevitz et al. 2012).
A novel in vitro allometric scaling methodology for aldehyde oxidase substrates to enable selection of appropriate species for traditional allometry
Published in Xenobiotica, 2018
Rachel D. Crouch, J. Matthew Hutzler, J. Scott Daniels
A high Fm,AO (≥0.70) was estimated for O6-benzylguanine in all species except rat, mouse and minipig, which could not be determined due to low turnover of the compound. As was the case for zaleplon in rat S9 incubations, a lack of measurable turnover of O6-benzylguanine in rat, mouse and minipig S9 incubations in the presence of both NADPH and hydralazine as well as incubations absent NADPH prevented estimation of Fm,AO.