title: Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients.
abstract: Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m(-2), followed by a fixed dose of 5.0 g m(-2) treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m(-2) gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m(-2) gemcitabine combined with 5.0 g m(-2) treosulfan.
authors.affiliation: Oncology Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. pippa.corrie@addenbrookes.nhs.uk
authors.forename: P G
authors.initials: PG
authors.lastname: Corrie
authors.forename: J
authors.initials: J
authors.lastname: Shaw
authors.forename: V J
authors.initials: VJ
authors.lastname: Spanswick
authors.forename: R
authors.initials: R
authors.lastname: Sehmbi
authors.forename: A
authors.initials: A
authors.lastname: Jonson
authors.forename: A
authors.initials: A
authors.lastname: Mayer
authors.forename: R
authors.initials: R
authors.lastname: Bulusu
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: I A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D020552:Comet Assay; D004249:DNA Damage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; C018404:treosulfan; D002066:Busulfan; D000093542:Gemcitabine