Clinical and in vitro studies of the correlation between MGMT and the effect of streptozocin in pancreatic NET

Cancer Chemother Pharmacol. 2019 Jan;83(1):43-52. doi: 10.1007/s00280-018-3700-y. Epub 2018 Oct 11.

Abstract

Purpose: This study aimed to determine the correlation between DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) status and the response to streptozocin in advanced well-differentiated pancreatic neuroendocrine tumors (WD panNETs).

Methods: To test the hypothesis that MGMT deficiency was required for an alkylating drug response, we retrospectively reviewed the response of 13 patients with WD panNETs to alkylating agents in relation to MGMT status. We also studied MGMT expression in streptozocin resistance using panNET cell lines.

Results: The cohort included 54% of patients with and 46% without MGMT expression. Among these, 83.3% (5/6) of MGMT-negative cases showed a partial response to streptozocin. In contrast, only 14.2% (1/7) of MGMT-positive cases showed a partial response (P = 0.013). Induced expression of MGMT in BON1 cells (a panNET cell line with undetectable endogenous MGMT) produced streptozocin resistance. Knockdown of MGMT in QGP1 cells, which express MGMT endogenously, did not alter the response to streptozocin.

Conclusions: We observed a relationship between MGMT status and streptozocin response in both patients and cell culture. Despite limited cases examined, high concordance of negative expression of MGMT and response to streptozocin treatment suggest that MGMT expression can be a potential biomarker for this treatment.

Keywords: BON1; MGMT; Methylation; Pancreatic neuroendocrine tumors; Streptozocin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibiotics, Antineoplastic / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • DNA Modification Methylases / metabolism*
  • DNA Repair Enzymes / metabolism*
  • Drug Resistance, Neoplasm
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Retrospective Studies
  • Streptozocin / therapeutic use*
  • Survival Rate
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Biomarkers, Tumor
  • Tumor Suppressor Proteins
  • Streptozocin
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes