O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer

Rifat Hasina, Mosmi Surati, Ichiro Kawada, Qudsia Arif, George Carey, Rajani Kanteti, Aliya Husain, Mark Ferguson, Everett Vokes, Victoria Villaflor, Ravi Salgia

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. Methods: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine- deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized. Results: Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC 50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%. Conclusion: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.

Original languageEnglish
Article number120632
JournalJournal of Carcinogenesis
Volume12
DOIs
Publication statusPublished - 2013 Jan 1
Externally publishedYes

Fingerprint

temozolomide
Methyltransferases
Esophageal Neoplasms
Methylation
DNA
Cell Line
Protein Methyltransferases
Heterografts
Squamous Cell Carcinoma
Neoplasms
Adenocarcinoma
Therapeutics
Platinum Compounds
Alkylating Agents
O-(6)-methylguanine
Cell Survival
Histology
Biomarkers

Keywords

  • Alkylating agents
  • deoxyribonucleic acid repair genes
  • esophageal cancer
  • in vivo pre-clinical
  • O-6-methylguanine-deoxyribonucleic acid methyltransferase hypermethylation
  • response to treatment
  • temozolomide

ASJC Scopus subject areas

  • Cancer Research
  • Health, Toxicology and Mutagenesis
  • Oncology

Cite this

O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer. / Hasina, Rifat; Surati, Mosmi; Kawada, Ichiro; Arif, Qudsia; Carey, George; Kanteti, Rajani; Husain, Aliya; Ferguson, Mark; Vokes, Everett; Villaflor, Victoria; Salgia, Ravi.

In: Journal of Carcinogenesis, Vol. 12, 120632, 01.01.2013.

Research output: Contribution to journalArticle

Hasina, R, Surati, M, Kawada, I, Arif, Q, Carey, G, Kanteti, R, Husain, A, Ferguson, M, Vokes, E, Villaflor, V & Salgia, R 2013, 'O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer', Journal of Carcinogenesis, vol. 12, 120632. https://doi.org/10.4103/1477-3163.120632
Hasina, Rifat ; Surati, Mosmi ; Kawada, Ichiro ; Arif, Qudsia ; Carey, George ; Kanteti, Rajani ; Husain, Aliya ; Ferguson, Mark ; Vokes, Everett ; Villaflor, Victoria ; Salgia, Ravi. / O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer. In: Journal of Carcinogenesis. 2013 ; Vol. 12.
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abstract = "Background: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. Methods: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine- deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized. Results: Nearly 71{\%} (12/17) of adenocarcinoma and 38{\%} (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC 50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60{\%}. Conclusion: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.",
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T1 - O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer

AU - Hasina, Rifat

AU - Surati, Mosmi

AU - Kawada, Ichiro

AU - Arif, Qudsia

AU - Carey, George

AU - Kanteti, Rajani

AU - Husain, Aliya

AU - Ferguson, Mark

AU - Vokes, Everett

AU - Villaflor, Victoria

AU - Salgia, Ravi

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Background: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. Methods: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine- deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized. Results: Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC 50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%. Conclusion: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.

AB - Background: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. Methods: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine- deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized. Results: Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC 50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%. Conclusion: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.

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KW - deoxyribonucleic acid repair genes

KW - esophageal cancer

KW - in vivo pre-clinical

KW - O-6-methylguanine-deoxyribonucleic acid methyltransferase hypermethylation

KW - response to treatment

KW - temozolomide

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