Endocrine Abstracts

Background: Temozolomide (TMZ) has been suggested as a treatment option for patients with pancreatic neuroendocrine tumours (PNETs). The tumour response to TMZ has been linked to expression levels of O6-methylguanine-DNA methyltransferase (MGMT) and components of the mismatch repair (MMR) system. However, there is no in vitro data on TMZ sensitivity and the expression of MGMT and MMR components in PNETs. Moreover, the effect of TMZ exposure on chemosensitivity and expression of MGMT and MRR components in PNET cell lines is unknown.

Methods: Two PNET cell lines, BON-1 and QGP-1, were used to determine TMZ sensitivity. TMZ resistance was induced by exposing cells to three 24-hour challenges with increasing doses of TMZ, each followed by a two week drug-free period. The effect of TMZ on cell growth, transcription of MGMT and MMR components (MLH1, MSH2, MSH6, PMS2), apoptosis induction and cell cycle was assessed.

Results: BON-1 were more sensitive to TMZ, compared to QGP-1, as reflected by a lower IC50 value of TMZ on cell growth (P<0.001). After a 24-hour exposure to 1x IC50 dose of TMZ, BON-1 cells develop TMZ resistance and maintain this phenotype. TMZ resistance was associated with increased MGMT expression and a decrease in TMZ-induced apoptosis and cell cycle arrest. In contrast to BON-1, the less TMZ sensitive QGP-1 cells have a higher base-line MGMT expression. Moreover, exposure of QGP-1 to TMZ did not result in increased resistance. In both cell lines, there was comparable expression of MMR components and exposure to TMZ was not associated with a shift in expression levels.

Conclusion: We demonstrated that TMZ sensitivity in human PNET cells is associated with the expression of MGMT. Furthermore, a single, short-term exposure to TMZ can induce sustained resistance in TMZ sensitive cell lines which is associated with increased MGMT expression.