scholarly journals Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Sadhak Sengupta ◽  
Jaclyn Marrinan ◽  
Caroline Frishman ◽  
Prakash Sampath
Keyword(s):  
Immune Response ◽  
Malignant Glioma ◽  
Dna Methyltransferase ◽  
Opportunistic Infections ◽  
Immune Surveillance ◽  
Drug Resistant ◽  
Methylguanine Dna Methyltransferase ◽  
Drug Resistant Mutation ◽  
Resistant Mutation

Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.

scholarly journals The role of direct DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) in high grade malignant glioma

2014 ◽  
Vol 7 (Suppl 1) ◽  
pp. P8
Author(s):  
M Jeru Manoj ◽  
G K Chetan ◽  
KVL Rao ◽  
HN Venkatesh ◽  
MK Sibin ◽  
...  
Keyword(s):  
Dna Repair ◽  
Malignant Glioma ◽  
Dna Methyltransferase ◽  
High Grade ◽  
Repair Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Dna Repair Gene

scholarly journals Systematic profiling of ATP response to acquired drug-resistant EGFR family kinase mutations

2020 ◽  
Vol 85 (10) ◽  
pp. 1265-1278
Author(s):  
Dingwa Zhang ◽  
Deyong He ◽  
Xiaoliang Pan ◽  
Lijun Liu
Keyword(s):  
Generic Drug ◽  
Human Cancer ◽  
Kinase Assay ◽  
Drug Resistant ◽  
Missense Mutations ◽  
Surface Plasmon Resonance Analysis ◽  
Competitive Inhibitors ◽  
Drug Resistant Mutation ◽  
Egfr Family ◽  
Resistant Mutation

Kinase-targeted cancer therapy (KTCT) with ATP-competitive inhibitors has been widely applied in clinics. However, a number of kinase missense mutations were observed to confer acquired drug resistance during therapy, largely limiting the clinical application of kinase inhibitors in KTCT. Instead of directly influencing inhibitor binding, kinase mutations can also cause generic resistance to ATP-competitive inhibitors by increasing ATP affinity. Herein, the intermolecular interaction of the ATP molecule with clinically observed drug-resistant EGFR family kinase mutations involved in human cancer are systematically characterize. Rigorous quantum mechanics/molecular mechanics (QM/MM) calculation and empirical Poisson?Boltzmann/surface area (PB/SA) analysis as well as in vitro kinase assay and surface plasmon resonance analysis were integrated to explore the binding capability of ATP to mutant residues in the structural context of the kinase domain, which resulted in a comprehensive profile of ATP response to acquired drug-resistant mutations of four EGFR family kinases (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4). From the profile, it was possible to identify those potent mutations that may influence ATP binding significantly; such mutations are potential candidates to cause generic resistance for ATP-competitive inhibitors. Consequently, the well documented generic drug-resistant mutation EGFR T790M and its counterpart ErbB2 T798M are found to increase ATP affinity by establishing an additional S?? interaction between the side-chain thioether group of the mutant Met residue and the aromatic adenine moiety of the ATP molecule, while EGFR D761Y is identified as a new generic drug-resistant mutation that can increase ATP affinity by eliminating unfavorable electrostatic repulsion. In contrast, ErbB2 K753E and T768I are considered to be two generic drug-sensitive mutations that can decrease ATP affinity by unfavorable charge reversal and by impairing favorable polar interaction, respectively. In addition, the EGFR L858R mutation is located at the kinase activation loop and nearby the kinase active site, thus largely complicating the multiply dependent relationship of kinase, ATP and inhibitor, which therefore exhibits divergent effects on different tested inhibitors.

scholarly journals Role of O6-methylguanine-DNA methyltransferase and p53 in response of neuroblastoma cells to an alkylating agent temozolomide

2018 ◽  
Vol 99 (1) ◽  
pp. 47-53
Author(s):  
R R Khusnutdinov ◽  
S V Boychuk
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agent ◽  
Neuroblastoma Cells ◽  
Methylguanine Dna Methyltransferase

Цель. Изучить роль белка р53 и О6-метилгуанин-ДНК-метилтрансферазы в чувствительности клеток нейробластомы к действию темозоломида. Методы. Исследование проводили на клеточной линии нейробластомы SK.N.SH, культивируемой в среде DMEM с добавлением эмбриональной телячьей сыворотки и антибиотиков пенициллина-стрептомицина в стандартных условиях (37 °C и 5% СО2). Клетки инкубировали с алкилирующим агентом темозоломидом в течение 48-72 ч. В ряде случаев осуществляли преинкубацию клеток в течение 2 ч с О6-бензилгуанином (ингибитором О6-метилгуанин-ДНК-метилтрансферазы) или нутлином-3а (реактиватором р53). Пролиферативную активность оценивали с помощью системы многопараметрического анализа клеточных культур (RTCA iCELLigence), а также колориметрического MTS-теста. Экспрессию белков определяли методом иммуноблоттинга с использованием соответствующих моноклональных антител. Результаты. Реактивация белка р53 приводила к значительному снижению скорости пролиферации клеток линии SK.N.SH. Цитотоксический эффект данного препарата более выражен по сравнению с темозоломидом, считающимся препаратом выбора при проведении химиотерапии пациентам с мультиформной глиобластомой и нейробластомой. Ингибирование О6-метилгуанин-ДНК-метилтрансферазы также приводило к усилению цитотоксического эффекта темозоломида, тем не менее, цитотоксический эффект химиопрепарата был менее выраженным по сравнению с действием темозоломида на фоне реактивации белка р53. Вывод. Для оценки чувствительности клеток нейробластомы к действию алкилирующего препарата темозоломида функциональное состояние белка р53 в опухолевых клетках служит более важным прогностическим критерием по сравнению с уровнем экспрессии О6-метилгуанин-ДНК-метилтрансферазы; кроме того, реактивация белка р53 приводит к снижению скорости пролиферации клеток нейробластомы линии SK.N.SH и их гибели по механизму апоптоза.

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