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

Rai, Roopa; Banerjee, Monali; Wong, David G.; McCullagh, Emma; Gupta, Ashu; Tripathi, Shailendra; Riquelme, Eduardo; Jangir, Ramnivas; Yadav, Shyamraj; Raja, Mohd.; Melkani, Pankaj; Dixit, Vikas; Patil, U. K.; Shrivastava, Ritesh; Middya, Sandip; Olivares, Felipe; Guerrero, Julien; Surya, Arjun; Pham, Son M.; Bernales, Sebastián; Protter, Andrew A.; Hung, David T.; Chakravarty, Sarvajit

doi:10.1016/j.bmcl.2016.08.064

Cited by 13 publications

(13 citation statements)

References 15 publications

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“…Information on TMZ for animal experiments see [20,[41][42][43][44][45]. Table according to [31,[33][34][35]40,[46][47][48][49][50][51][52][53]. Dash) data not reported; (*) range of absolute area under the curve (AUC) brain or cerebrospinal fluid (CSF)/plasma ratio; (**) range of mean AUC brain or CSF/plasma ratio.…”

Section: Theophrastus Bombast Von Hohenheimmentioning

confidence: 99%

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Herbener¹,

Burster

Goreth³

et al. 2020

Biomedicines

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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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Section: Theophrastus Bombast Von Hohenheimmentioning

confidence: 99%

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Herbener¹,

Burster

Goreth³

et al. 2020

Biomedicines

View full text Add to dashboard Cite

show abstract

“…For example, an ideal MGMT inhibitor would be a molecule that could specifically dock in the MGMT amino acid sequence (Pro-Cys-His-Arg) that contains the active site ( 110 ). Second, novel imidazotetrazine analogs have been recently tested in orthotopic mouse xenografts that showed significantly better brain to plasma ratios compared with TMZ ( 111 ). Researchers used imidazotetrazine analogs that acted in the same manner as TMZ yet treatment using these compounds showed lipophilic binding to the entire brain tissue, reducing its availability to the target tumor cells.…”

Section: Future Directionsmentioning

confidence: 99%

“…Researchers used imidazotetrazine analogs that acted in the same manner as TMZ yet treatment using these compounds showed lipophilic binding to the entire brain tissue, reducing its availability to the target tumor cells. Nevertheless, chemical modifications are attainable and are under investigation ( 111 ). Future research should target the competition of TMZ with the P-glycoprotein (P-gp) which acts as a drug efflux pump that expels the drugs from the cell, reducing its effectiveness in the membrane of tumor cells.…”

Section: Future Directionsmentioning

confidence: 99%

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions

et al. 2018

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Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.

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“…42,51,52 To our knowledge, only one derivative has outperformed TMZ in an intracranial murine model of GBM, bestowing a modest 10% increase in median survival. 53 Clearly, the interplay between retaining the favorable properties that have kept TMZ as frontline treatment for GBM and modulating its structure is not trivial.…”

Section: Resultsmentioning

confidence: 88%

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

et al. 2018

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Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

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

Cited by 13 publications

References 15 publications

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

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