Multicenter Phase II Trial of Temozolomide in Mycosis Fungoides/Sézary Syndrome: Correlation with O6-Methylguanine-DNA Methyltransferase and Mismatch Repair Proteins

Abstract

Purpose Temozolomide (TMZ) is an oral derivative of dacarbazine that induces DNA damage by methylating nucleotide bases. Resistance has been associated with high levels of O6-methylguanine-DNA methyltransferase (MGMT). Malignant CD4+ T cells of patients with mycosis fungoides/Sézary syndrome (MF/SS) have been shown to have low levels of MGMT and may be particularly sensitive to this methylator. Experimental Design The efficacy of TMZ was evaluated in a multicenter phase II trial of patients with advanced stages of MF/SS. TMZ was given orally at daily doses of 200 mg/m2 for 5 days every 28 days. MGMT and mismatch repair protein expression was assessed by quantitative immunofluorescence and immunohistochemistry in skin and blood samples. Results Twenty-six patients (stages IB–IVB) were evaluable for response. Patients had a median of four prior treatments. Median follow-up time was 19 months (range, 1–95). The overall response was 27% with two complete remissions (8%) and five partial remissions (19%). Median disease-free survival was 4 months. The median overall survival was 24 months. The most frequent toxicities included constitutional symptoms, gastrointestinal symptoms, and hematologic toxicities. Treatment was discontinued in three patients following grade 3 thrombocytopenia, lymphopenia, and skin reaction. The relationship between pretreatment MGMT and mutL homolog 1 (MLH1)/mutS homolog 2 (MSH2) mismatch repair protein expression levels in skin biopsies of cutaneous lesions and clinical response to TMZ were evaluated. Conclusions Pretreatment levels of MGMT and MLH1/MSH2 protein levels are not predictive of response to TMZ in MF/SS, suggesting that other resistance mechanisms are important.

Determination of Protein-Protein Interaction for Cancer Control via Mass Spectrometry and Nanoconductimetry of NAPPA SNAP Arrays: An Overview

“…Unfortunately, some cells can escape from this mechanism producing a protein known as O 6 -alkylguanine DNA alkyltransferase (AGT), encoded by the O 6 -methylguanine-DNA methyltransferase (MGMT) gene. Recently, scientists have been able to find and characterize some biomarkers of resistance to temozolomide, such as MLH1, which is also an important marker of survival rate in patients with glioblastoma [21][22][23][24][25].…”

Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma

“…75 In the most recent trial, which examined TMZ at 200 mg/m 2 for 5 days every 28 days in stage IB-IVA MF/SS, there was an ORR in 7 of 26 (27%) in patients with treatment refractory disease. 76 Response was assessed at the 2nd cycle and responders were treated with TMZ through 1 year. The median disease-free survival, however, was only 4 months.…”

Drug-Protein Interactions for Clinical Research by Nucleic Acid Programmable Protein Arrays-Quartz Crystal Microbalance with Dissipation Factor Monitoring Nanoconductometric Assay

“…Recently, scientists have been able to find and characterize some biomarkers of resistance to TMZ, such as MLH1, which is also an important marker of survival rate in patients with glioblastoma (Mirzoeva et al, 2006;Querfeld et al, 2011;Shinsato et al, 2013;Stark et al, 2010;von Bueren et al, 2012).…”

“…Temodar, Temodal and Temcad) is an oral antiblastic, chemically being the imidazotetrazine derivative of the alkylating/methylating agent dacarbazine and it undergoes rapid chemical conversion in the systemic circulation at physiological pH to the active compound, 3-Methyl-(triazen-1-yl) Imidazole-4-Carboxamide (MTIC). TMZ is useful for treating brain tumors, such as the GBM, the relapsed Grade III anaplastic astrocytoma, especially if nitrosourea-and procarbazine-refractory, as well as skin cancers, like the melanoma and the fungoides mycosis/Sézary syndrome (Querfeld et al, 2011). It is currently in evaluation for the treatment of other tumors, such as the relapsed primary CNS lymphoma, recurrent glioma and oligodendroglioma (in the last case, replacing the classical regimen Procarbazine-LomustineVincristine (PCV)).…”