Spieth Konstanze, Kaufmann Roland, Gille Jens
Department of Dermatology, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Cancer Chemother Pharmacol. 2003 Nov;52(5):377-82. doi: 10.1007/s00280-003-0678-9. Epub 2003 Jul 22.
The safety and efficacy of oral metronomic low-dose treosulfan chemotherapy in combination with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib as a compound with antiangiogenic potential, a therapeutic regimen optimally targeting endothelial cells instead of tumor cells, were assessed in pretreated advanced melanoma patients.
Endothelial cells were analyzed for proliferation, apoptosis and cytotoxicity in response to increasing concentrations of treosulfan, either in the absence or presence of COX-2 inhibitor, to determine whether inhibition of COX-2 enhanced the effect of treosulfan on cell function. In a clinical pilot study, 12 consecutive patients with pretreated advanced melanoma, meeting the eligibility criteria were enrolled. Patients received combined daily treosulfan chemotherapy (500 mg) with rofecoxib (25 mg). Metastatic lesions were assessed every 12 weeks. Patients with responsive or stable disease were eligible for a further 12-week treatment period. Response criteria according to the WHO handbook for reporting results of cancer treatment were applied. Side effects were classified according to the National Cancer Institute's Common Toxicity Criteria v2.0.
At noncytotoxic concentrations, treosulfan inhibited endothelial cell proliferation in a dose-dependent fashion. Simultaneous inhibition of COX-2 significantly increased the extent to which treosulfan suppressed cell proliferation, without inducing cytotoxicity. In the pilot study in which 12 patients were treated, toxicity was mild; only hematologic toxicity of grade II was seen. An objective response was noted in one patient, and four patients showed stabilization of their disease for 24 weeks (one) and 36 weeks (three). The patient who had a partial response subsequently showed stable disease for 48 weeks. The median survival time was 13 months.
As increases in response rates following polychemo- or biochemotherapy have not been shown to correlate with prolongation in overall survival, more durable control of metastatic melanoma represents an attractive therapeutic goal. Thus, regimens scheduled to primarily target endothelial cells may potentially provide a palliative alternative that preserves quality of life in the absence of significant treatment-related toxicity.
在预处理的晚期黑色素瘤患者中评估口服小剂量规律环磷酰胺化疗联合环氧合酶 -2（COX-2）抑制剂罗非昔布作为一种具有抗血管生成潜力的化合物、一种最佳靶向内皮细胞而非肿瘤细胞的治疗方案的安全性和有效性。
分析内皮细胞在不存在或存在COX-2抑制剂的情况下对不同浓度环磷酰胺的增殖、凋亡和细胞毒性反应，以确定COX-2抑制是否增强环磷酰胺对细胞功能的影响。在一项临床初步研究中，连续纳入12例符合入选标准的预处理晚期黑色素瘤患者。患者接受每日环磷酰胺化疗（500mg）联合罗非昔布（25mg）治疗。每12周评估转移病灶。疾病有反应或稳定的患者有资格接受进一步12周的治疗期。应用世界卫生组织癌症治疗结果报告手册中的反应标准。根据美国国立癌症研究所的常见毒性标准v2.0对副作用进行分类。
在无细胞毒性浓度下，环磷酰胺以剂量依赖性方式抑制内皮细胞增殖。同时抑制COX-2显著增加了环磷酰胺抑制细胞增殖的程度，且未诱导细胞毒性。在12例患者接受治疗的初步研究中，毒性较轻；仅观察到2级血液学毒性。1例患者出现客观反应，4例患者疾病稳定24周（1例）和36周（3例）。出现部分反应的患者随后疾病稳定48周。中位生存时间为13个月。
由于多药化疗或生物化疗后反应率的提高尚未显示与总生存期延长相关，对转移性黑色素瘤进行更持久的控制是一个有吸引力的治疗目标。因此，主要靶向内皮细胞的治疗方案可能潜在地提供一种姑息性替代方案，在没有明显治疗相关毒性的情况下维持生活质量。
