Schallreuter K U, Wenzel E, Brassow F W, Berger J, Breitbart E W, Teichmann W
Department of Dermatology, University of Hamburg, Federal Republic of Germany.
Cancer Chemother Pharmacol. 1991;29(1):85-7. doi: 10.1007/BF00686343.
To date, dacarbazine (DTIC) has been the most effective drug in the treatment of advanced metastatic melanoma, achieving response rates of up to 28% (mean, 21%). Multidrug responses were generally no better than those obtained using monotherapy. A quite promising clinical trial was conducted using the new nitrosourea fotemustine. A total of 19 patients presenting with advanced malignant melanoma (clinical stage IV according to the 1987 UICC classification system) underwent treatment involving a more rapid infusion of the drug and a reduction in the rest period from 5 to 3 weeks. This monotherapy with fotemustine yielded two complete responses and seven partial responses; in addition, four patients showed no change and six cases progressed after the induction cycle (median duration of response to date, 7.6 months, including four cases that have not relapsed). Fotemustine was well tolerated by the patients, with the only mild side effects being thrombocytopenia, leukocytopenia and easily controlled nausea/vomiting. Preclinical studies performed previously indicated that fotemustine inhibits enzymes involved in the ribonucleotide reduction pathway (i.e. DNA synthesis), whereby responding patients (n = 3) appeared to favor the thioredoxin reductase/thioredoxin electron transfer to ribonucleotide reductase, whereas non-responders (n = 4) expressed the alternate glutathione reductase/glutaredoxin mechanism. The 47% response rate obtained in these studies vs the 24% reported previously for fotemustine may reflect variations in enzymes in the ribonucleotide reduction pathway in different patients. However, the efficacy of fotemustine against advanced melanoma warrants more extensive trials of this drug, especially since the quality of life of the patients during and after chemotherapy was not severely affected.
迄今为止，达卡巴嗪（DTIC）一直是治疗晚期转移性黑色素瘤最有效的药物，有效率高达28%（平均为21%）。联合用药的疗效一般并不优于单一疗法。一项使用新型亚硝基脲福莫司汀的临床试验颇具前景。共有19例晚期恶性黑色素瘤患者（根据1987年国际抗癌联盟分类系统为临床IV期）接受了治疗，治疗中加快了药物输注速度，并将休息期从5周缩短至3周。福莫司汀单一疗法产生了2例完全缓解和7例部分缓解；此外，4例患者病情无变化，6例在诱导周期后病情进展（截至目前的中位缓解持续时间为7.6个月，包括4例未复发的患者）。患者对福莫司汀耐受性良好，仅出现轻度副作用，如血小板减少、白细胞减少以及易于控制的恶心/呕吐。先前进行的临床前研究表明，福莫司汀可抑制参与核糖核苷酸还原途径（即DNA合成）的酶，由此，有反应的患者（n = 3）似乎更倾向于硫氧还蛋白还原酶/硫氧还蛋白向核糖核苷酸还原酶的电子传递，而无反应的患者（n = 4）则表现出另一种谷胱甘肽还原酶/谷氧还蛋白机制。这些研究中获得的47%的有效率与先前报道的福莫司汀24%的有效率相比，可能反映了不同患者核糖核苷酸还原途径中酶的差异。然而，福莫司汀治疗晚期黑色素瘤的疗效值得对该药物进行更广泛的试验，特别是因为化疗期间及化疗后患者的生活质量并未受到严重影响。
