Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients.
Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients.
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第一阶段的试验结合了晚期皮肤和紫veal黑色素瘤患者中的吉西他滨和treosulfan。
DOI：
10.1038/sj.bjc.6602586
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发表时间：
2005-06-06
影响因子：
8.8
通讯作者：
Cree, IA
中科院分区：
文献类型：
--
作者：
Corrie, PG;Shaw, J;Spanswick, VJ;Sehmbi, R;Jonson, A;Mayer, A;Bulusu, R;Hartley, JA;Cree, IA
吉西他滨和曲奥舒凡是DNA损伤剂。临床前研究表明，当黑色素瘤细胞同时暴露于两种药物时，存在协同作用。我们在晚期黑色素瘤患者中进行了一项I期试验，以确定吉西他滨与曲舒凡联合治疗的最佳剂量。三名患者的队列接受了剂量递增的吉西他滨，从0.5 g m−2开始，然后在21天周期的第一天接受固定剂量的5.0 g m−2曲硫凡。患者在随后的两种药物周期之前交替接受第一个周期的吉西他滨或曲舒凡单药治疗。在周期1和周期2的不同时间点收集外周血淋巴细胞，直至治疗后48 h。单细胞凝胶电泳（彗星）测定用于测量化疗诱导的DNA损伤。共入组27例患者，未观察到客观缓解，但2例葡萄膜黑色素瘤患者有轻微缓解。在3.0 g m−2吉西他滨时达到剂量限制性骨髓抑制。吉西他滨给药后4 h检测到DNA单链断裂，24 h修复。使用曲奥磺凡4小时后检测到DNA链间交联，48小时后完全消除。联合化疗后，曲硫烷诱导的DNA交联持续存在，治疗后48小时仍可检测到，支持吉西他滨增强曲硫烷诱导的细胞毒性的假设。推荐的进一步研究方案是2.5 g m−2吉西他滨联合5.0 g m−2曲舒凡。
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.
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影响因子：
8.8
作者：
Neale, MH;Myatt, N;Cree, IA;Kurbacher, CM;Foss, AJE;Hungerford, JL;Plowman, PN
通讯作者：
Plowman, PN
影响因子：
2.3
作者：
Pföhler, C;Cree, IA;Reinhold, U
通讯作者：
Reinhold, U
DOI：
10.1385/1-59259-687-8:143
发表时间：
1999-01-01
期刊：
CYTOTOXIC DRUG RESISTANCE MECHANISMS
影响因子：
--
作者：
Spanswick, VJ;Hartley, JM;Hartley, JA
通讯作者：
Hartley, JA
Treosulfan的DNA烷基化和链间交联。
影响因子：
8.8
作者：
Hartley, J A;O'Hare, C C;Baumgart, J
通讯作者：
Baumgart, J
影响因子：
2.3
作者：
Cree, IA;Neale, MH;Andreotti, PE
通讯作者：
Andreotti, PE