title: Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Department of Dermatology, Northwestern University, Chicago, Illinois, USA.
authors: Christiane
authors: C
authors: Querfeld
authors: Steven T
authors: ST
authors: Rosen
authors: Joan
authors: J
authors: Guitart
authors: Alfred
authors: A
authors: Rademaker
authors: David S
authors: DS
authors: Pezen
authors: M Eileen
authors: ME
authors: Dolan
authors: Joseph
authors: J
authors: Baron
authors: Daniel B
authors: DB
authors: Yarosh
authors: Francine
authors: F
authors: Foss
authors: Timothy M
authors: TM
authors: Kuzel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004249:DNA Damage; D053843:DNA Mismatch Repair / Q000187:drug effects*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000097:blood; D009182:Mycosis Fungoides / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000097:blood; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D012751:Sezary Syndrome / Q000188:drug therapy*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000077204:Temozolomide