Temozolomide chemoresistance heterogeneity in melanoma with different treatment regimens

• DOI: 10.1097/cmr.0b013e328345af95
• Publication Date: 2011-03-31T02:39:23Z
• Authors: Lars Boeckmann; Ann-Christin Nickel; Christiane Kuschal; Annika Schaefer; Kai-Martin Thoms; Michael P. Schön; Jürgen Thomale; Steffen Emmert
• Keywords: Temozolomide; O-6-methylguanine-DNA methyltransferase

The efficacy of temozolomide in melanoma treatment is low (response rate <20%) and may depend on the activity O6-methylguanine DNA methyltransferase (MGMT) mismatch repair. We identified cell lines with different sensitivities to single versus prolonged clinical dosing regimens assessed a variety potential resistance mechanisms using this model. measured mRNA expression promoter methylation MGMT essential repair genes (MLH1, MSH2). Cell cycle distribution, apoptosis/necrosis induction, O6-methylguanine-adduct formation, ABCB1 gene were assessed. found that three lines, MelA, MelB, MelC, more sensitive dose regimen than regimen, which would be expected exhibit higher cytotoxicity. KAII LIBR sensitivity was regard as expected. Only MelC expressed MGMT. Gene correlated well methylation. Temozolomide exposure did not alter expression. Different caused neither by delayed apoptosis induction due early arrest nor formation or efflux transporter most resistant line rapid elimination adducts. This good agreement its accumulated adducts after second contrast other lines. conclude adduct accumulation are relevant factors chemosensitivity. Considering individualized either quantification chemosensitivity testing seems worthwhile clinically.