Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase

Arai, Hajime; Yamauchi, Takahiro; Uzui, Kanako; Ueda, Takanori

doi:10.3892/ol.2015.3307

Cited by 3 publications

(3 citation statements)

References 22 publications

(40 reference statements)

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“…Being highly reactive molecules, the alkylating agents induce cell death by binding to DNA 10 . There are two types of alkylating drugs: monofunctional, including temozolomide and dacarbazine, which produce a cross-link between adjacent strands of DNA, and bifunctional, such as melphalan, which produces interstrand and intrastrand cross-links; melphalan also alkylates RNA and protein structures 11 . DNA lesions produced by melphalan require several and complex repair mechanisms 12 .…”

Section: Introductionmentioning

confidence: 99%

MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

et al. 2017

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Approximately 25% of melanoma patients with locoregional metastases are nonresponsive to new molecular target therapy and immunotherapy. When metastases are located in the pelvis, melphalan hypoxic perfusion can be an optional treatment. Because methylation of MGMT promoter increases the efficacy of alkylating agents, studies on melanoma outcome of patients treated with melphalan regional chemotherapy should consider this epigenetic change. This study aims to evaluate whether the survival of stage III melanoma patients treated with melphalan regional chemotherapy may be correlated with MGMT methylation status. The metastatic tissues of 27 stage III melanoma patients with locoregional metastases located in the pelvis subjected to melphalan hypoxic pelvic perfusion were examined. The methylation status of the MGMT promoter was investigated by MS-MLPA probes analysis and the presence of the BRAF V600E mutation was analyzed by CAST-PCR. The median survival times were estimated using the Kaplan–Meier curves and were stratified according to the clinicopathological characteristics of patients and lesions. The overall median survival time was 17 months. The 1-year, 3-year, and 5-year survival rates were 66.7, 18.5, and 7.4%, respectively. Disease stage, burden, and percentage of MGMT methylation significantly affected survival. We estimated an MGMT promoter methylation cut-off of at least 14%, which was significantly associated with a longer survival after melphalan regional chemotherapy. Our data suggest that MGMT promoter methylation could be an important factor in determining which melanoma patients should receive melphalan regional chemotherapy, but its prognostic significance in the routine clinical setting needs to be clarified in a larger study.

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Section: Introductionmentioning

confidence: 99%

MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

et al. 2017

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“…Several patients presented with complete responses, although it was also recognized that the best response to TMZ is dependent on low, or absent, expression of MGMT in patients’ tumor cells [ 20 , 21 , 22 , 25 ]. The protective effect of MGMT against TMZ is particularly detrimental in AML, because the majority of AML patients present with significant MGMT expression in their tumor tissue [ 26 ], consistent with laboratory studies that only 25% of leukemia cells harbor low levels of MGMT [ 27 ], and inhibition of MGMT in vitro greatly sensitizes leukemia cells to TMZ [ 28 ].…”

Section: Introductionmentioning

confidence: 61%

NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Chen

Minea

Swenson

et al. 2022

Cancers

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Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML.

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“…As a result of alkylation, the DNA chain undergoes structural changes that afect both transcription and replication processes [3]. Temozolomide (I), carmustine (II), and cyclophosphamide (III) are three famous examples of DNA alkylating drugs (Figure 1) [4].…”

Section: Introductionmentioning

confidence: 99%

Novel Xanthene-1,8-dione Derivatives Containing the Benzylic Ether Tail as Potent Cytotoxic Agents: Design, Synthesis, In Vitro, and In Silico Studies

Ebadi,

Karimi,

Bahmani

et al. 2024

Journal of Chemistry

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Seventeen new xanthene-1,8-dione derivatives were synthesized and evaluated as cytotoxic agents against the lung carcinoma cell line (A549). Compound 9-(4-(benzyloxy)phenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (4a) showed good cytotoxic effects (34.59 μM) in comparison to cis-platin. Docking results showed 4a could interact with DNA as intercalation. Calculated ligand efficiency of compound 4a was more than daunomycin. Based on the results, it can be concluded that compound 4a is a suitable DNA binding agent.

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Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase

Cited by 3 publications

References 22 publications

MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Novel Xanthene-1,8-dione Derivatives Containing the Benzylic Ether Tail as Potent Cytotoxic Agents: Design, Synthesis, In Vitro, and In Silico Studies

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