Cancer Research and Treatment

Original Articles

To Use or Not to Use: Temozolomide in Elderly Patients with IDH Wild-Type MGMT Promoter Unmethylated Glioblastoma Treated with Radiotherapy: Chan Woo Wee, Joo Ho Lee, Hye In Lee, Jina Kim, Jong Hee Chang, Seok-Gu Kang, Eui Hyun Kim, Ju Hyung Moon, Jaeho Cho, Chul-Kee Park, Chae-Yong Kim, Kihwan Hwang, Hong In Yoon, In Ah Kim; Received September 27, 2024 Accepted November 8, 2024 Published online November 11, 2024; DOI: https://doi.org/10.4143/crt.2024.945 [Epub ahead of print]

Abstract PDF PubReader ePub: Purpose
This study aimed to identify a specific subgroup of patients among elderly glioblastoma patients aged 70 years or older with unmethylated O6-methylguanine-DNA methyltransferase promoters (eGBM-unmethylated) who would significantly benefit from the addition of temozolomide (TMZ) to radiotherapy (RT).
Materials and Methods
Newly diagnosed patients with Isocitrate dehydrogenase wild-type eGBM-unmethylated treated with RT were included in this multicenter analysis (n=182). RT dose was 45 Gy in 15 fractions (62.3%), 60 Gy in 30 fractions, or 61.2 Gy in 34 fractions. For patients treated with RT plus TMZ (60.4%), TMZ was administered concurrently with RT, followed by six adjuvant cycles. The primary endpoint was overall survival.
Results
During a median follow-up of 11.3 months for survivors, the median survival was 12.2 months. The median survival duration significantly improved with the addition of TMZ to RT compared with that with RT alone (13.6 months vs. 10.5 months, p=0.028). In the multivariable analysis adjusted for clinical, radiological, and genetic biomarkers, the addition of TMZ significantly improved overall survival (hazard ratio, 0.459; p=0.006). In subgroup analysis, median survival was especially improved by 4-5 months in patients with residual disease (p < 0.001), Karnofsky performance status ≥ 60 (p=0.033), and age ≤ 75 years (p=0.090). A significant benefit of TMZ was noted only in patients with two or three of the above factors (median survival, 14.1 months vs. 10.5 months; p=0.014).
Conclusion
The addition of TMZ significantly improved the survival of patients with eGBM-unmethylated treated with RT. The suggested criteria for the specific subgroup in these patients warrant external validation for clinical application.

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Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro: Hyeon Kang Koh, Soo Yeon Seo, Jin Ho Kim, Hak Jae Kim, Eui Kyu Chie, Seung-Ki Kim, Il Han Kim; Cancer Res Treat. 2019;51(2):696-705. Published online August 13, 2018; DOI: https://doi.org/10.4143/crt.2018.249

Abstract PDF PubReader ePub

Purpose
Glioblastoma, the most common brain tumor in adults, has poor prognosis. The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect.
Materials and Methods
Five human glioblastoma cells (U138MG, T98G, U251MG, U87MG, and U373MG) and one normal human astrocyte (NHA) cell were cultured and treated with DSF or 6MV X-rays (0, 2, 4, 6, and 8 Gy). For combined treatment, cells were treated with DSF before irradiation. Surviving fractions fit from cell survival based on colony forming ability. Apoptosis, DNA damage repair, and cell cycle distributionwere assayed bywestern blot for cleaved caspase-3, γH2AX staining, and flow cytometry, respectively.
Results
DSF induced radiosensitization in most of the glioblastoma cells, especially, in the cells with radioresistance as wildtype unmethylated promoter (MGMT-wt), but did not in normal NHA cell. DSF augmented or induced cleavage of caspase-3 in all cells after irradiation. DSF inhibited repair of radiation-induced DNA damage in MGMT-wt cells, but not in cells with methylated MGMT promoter. DSF abrogated radiation-induced G2/M arrest in T98G and U251MG cells.
Conclusion
Radiosensitivity of glioblastoma cells were preferentially enhanced by pre-irradiation DSF treatment compared to normal cell, especially radioresistant cells such as MGMT-wt cells. Induction of apoptosis or inhibition of DNA damage repair may underlie DSF-induced radiosensitization. Clinical benefit of combining DSF with radiotherapy should be investigated in the future.

Citations

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The role of KDM4A‐mediated histone methylation on temozolomide resistance in glioma cells through the HUWE1/ROCK2 axis
Xi‐Xi Li, Jia‐Kun Xu, Wei‐Jie Su, Hong‐Lin Wu, Kun Zhao, Chang‐Ming Zhang, Xiang‐Kun Chen, Li‐Xuan Yang
The Kaohsiung Journal of Medical Sciences.2024; 40(2): 161. CrossRef
Glioblastoma Therapy: Past, Present and Future
Elena Obrador, Paz Moreno-Murciano, María Oriol-Caballo, Rafael López-Blanch, Begoña Pineda, Julia Gutiérrez-Arroyo, Alba Loras, Luis Gonzalez-Bonet, Conrado Martinez-Cadenas, José Estrela, María Marqués-Torrejón
International Journal of Molecular Sciences.2024; 25(5): 2529. CrossRef
Exploring Disulfiram’s Anticancer Potential: PLGA Nano-Carriers for Prolonged Drug Delivery and Potential Improved Therapeutic Efficacy
Ibrahim Dumbuya, Ana Maria Pereira, Ibrahim Tolaymat, Adnan Al Dalaty, Basel Arafat, Matt Webster, Barbara Pierscionek, Mouhamad Khoder, Mohammad Najlah
Nanomaterials.2024; 14(13): 1133. CrossRef
Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma
Rafael Jiménez, Andrada Constantinescu, Muhube Yazir, Paula Alfonso-Triguero, Raquel Pequerul, Xavier Parés, Mileidys Pérez-Alea, Ana Paula Candiota, Jaume Farrés, Julia Lorenzo
International Journal of Molecular Sciences.2024; 25(21): 11512. CrossRef
Clinical, pharmacological, and formulation evaluation of disulfiram in the treatment of glioblastoma - a systematic literature review
Beáta-Mária Benkő, Dimitrios A. Lamprou, Anna Sebestyén, Romána Zelkó, István Sebe
Expert Opinion on Drug Delivery.2023; 20(4): 541. CrossRef
Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma
Katja Werlenius, Sara Kinhult, Tora Skeidsvoll Solheim, Henriette Magelssen, David Löfgren, Munila Mudaisi, Sofia Hylin, Jiri Bartek, Michael Strandéus, Magnus Lindskog, Havyan Bahroz Rashid, Louise Carstam, Sasha Gulati, Ole Solheim, Jiri Bartek, Øyvind
JAMA Network Open.2023; 6(3): e234149. CrossRef
Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways
YAPING GAN, TING LIU, WEIFENG FENG, LIANG WANG, LI LI, YINGXIA NING
Oncology Research.2023; 31(3): 333. CrossRef
Disulfiram/Copper induces antitumor activity against gastric cancer via the ROS/MAPK and NPL4 pathways
Yao Liu, Xin Guan, Meiling Wang, Naixue Wang, Yutong Chen, Baolei Li, Zhuxuan Xu, Fangwei Fu, Cheng Du, Zhendong Zheng
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Shiyu Zhong, Shengyu Liu, Xin Shi, Xudong Zhang, Kunhang Li, Guojun Liu, Lishuai Li, Shanwei Tao, Bowen Zheng, Weichen Sheng, Ziyin Ye, Qichen Xing, Qingqing Zhai, Lijie Ren, Ying Wu, Yijun Bao
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Antioxidant and Antiproliferative Activity of Finasteride against Glioblastoma Cells
Hyeon Ji Kim, Tae-Jun Kim, Yu Gyung Kim, Chaeeun Seong, Jin-Hwa Cho, Wanil Kim, Kyung-Ha Lee, Do-Yeon Kim
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Disulfiram Sensitizes a Therapeutic-Resistant Glioblastoma to the TGF-β Receptor Inhibitor
Chan-Chuan Liu, Cheng-Lin Wu, Meng-Xuan Lin, Chun-I Sze, Po-Wu Gean
International Journal of Molecular Sciences.2021; 22(19): 10496. CrossRef
Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
Lisa Zirjacks, Nicolai Stransky, Lukas Klumpp, Lukas Prause, Franziska Eckert, Daniel Zips, Sabine Schleicher, Rupert Handgretinger, Stephan M. Huber, Katrin Ganser
Biomolecules.2021; 11(11): 1561. CrossRef
The combination of disulfiram and copper for cancer treatment
Hong Li, Jingyu Wang, Chunfu Wu, Lihui Wang, Zhe-Sheng Chen, Wei Cui
Drug Discovery Today.2020; 25(6): 1099. CrossRef
Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme
Jinyeong Choi, Gaeun Kim, Su Bin Cho, Hyung-Jun Im
Journal of Nanobiotechnology.2020;[Epub] CrossRef
Disulfiram as a Therapeutic Agent for Metastatic Malignant Melanoma—Old Myth or New Logos?
Francisco Meraz-Torres, Sarah Plöger, Claus Garbe, Heike Niessner, Tobias Sinnberg
Cancers.2020; 12(12): 3538. CrossRef
Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents
Elmira Ekinci, Sagar Rohondia, Raheel Khan, Qingping P. Dou
Recent Patents on Anti-Cancer Drug Discovery.2019; 14(2): 113. CrossRef

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Concurrent Chemoradiotherapy with Temozolomide Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients: A Retrospective Multicenter Observation Study in Korea: Byung Sup Kim, Ho Jun Seol, Do-Hyun Nam, Chul-Kee Park, Il Han Kim, Tae Min Kim, Jeong Hoon Kim, Young Hyun Cho, Sang Min Yoon, Jong Hee Chang, Seok-Gu Kang, Eui Hyun Kim, Chang-Ok Suh, Tae-Young Jung, Kyung-Hwa Lee, Chae-Yong Kim, In Ah Kim, Chang-Ki Hong, Heon Yoo, Jin Hee Kim, Shin-Hyuk Kang, Min Kyu Kang, Eun-Young Kim, Sun-Hwan Kim, Dong-Sup Chung, Sun-Chul Hwang, Joon-Ho Song, Sung Jin Cho, Sun-Il Lee, Youn-Soo Lee, Kook-Jin Ahn, Se Hoon Kim, Do Hun Lim, Ho-Shin Gwak, Se-Hoon Lee, Yong-Kil Hong; Cancer Res Treat. 2017;49(1):193-203. Published online June 27, 2016; DOI: https://doi.org/10.4143/crt.2015.473

Abstract PDF PubReader ePub

Purpose
The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample.
Materials and Methods
A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively.
Results
After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients,respectively. The methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period.
Conclusion
Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

Citations

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Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression: Na-Hye Myong; Cancer Res Treat. 2010;42(2):95-100. Published online June 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.2.95

Abstract PDF PubReader ePub

Purpose

Functional inactivation of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene has been demonstrated as loss of MGMT protein and suggested that it plays an important role in primary human neoplasia, including lung cancer. It has also been reported to be associated with the G : C→A : T transition mutation in the p53 gene of lung cancer. The aims of this study were to investigate the role of MGMT expression loss and its prognostic significance in non-small cell lung carcinomas (NSCLCs), and its correlation with p53 overexpression as well as influence on patient survival.

Materials and Methods

112 surgically resected NSCLC specimens were reviewed by medical records for their clinicopathologic variables. Their tissue microarray blocks were immunostained with anti-human MGMT and p53 primary antibodies. Correlation between MGMT loss and the clinicopathologic prognostic factors, including p53 overexpression and the single or combined actions of MGMT loss and p53 overexpression on patient survival were statistically analyzed by SPSS15.0.

Results

Reduced or absent MGMT expression was found in 48 of 112 NSCLCs (43%), and significantly associated with nodal metastasis and squamous or undifferentiated cell types. Loss of MGMT expression was correlated with p53 overexpression in adenocarcinomas, but not in overall NSCLCs. Its solitary or combined actions with p53 overexpression did not have influence on patient survival.

Conclusion

Loss of MGMT expression is a relatively common event in NSCLCs and significantly associated with nodal metastasis and p53 overexpression, suggesting that it may play a major role in pulmonary carcinogenesis, and also in disease progression of NSCLCs.

Citations

Citations to this article as recorded by

O 6 -Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer?
Birgitta I. Hiddinga, Patrick Pauwels, Annelies Janssens, Jan P. van Meerbeeck
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Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours
Nicolas Bonello, James Sampson, John Burn, Ian J. Wilson, Gail McGrown, Geoff P. Margison, Mary Thorncroft, Philip Crossbie, Andrew C. Povey, Mauro Santibanez-Koref, Kevin Walters
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Kyung Eun Lee
Journal of Cancer Prevention.2013; 18(4): 351. CrossRef

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