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

12 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

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Health, Toxicology and Mutagenesis

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  • Cite this

    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, 12, [120632]. https://doi.org/10.4103/1477-3163.120632