Heterogeneity of chemosensitivity of metastatic cutaneous melanoma
Heterogeneity of chemosensitivity of metastatic cutaneous melanoma
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DOI：
10.1097/00001813-199906000-00002
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发表时间：
1999-06-01
影响因子：
2.3
通讯作者：
Andreotti, PE
中科院分区：
文献类型：
--
作者：
Cree, IA;Neale, MH;Andreotti, PE
晚期黑色素瘤预后差，化疗对大多数患者几乎没有好处。这可能与化疗敏感性的异质性以及对单个细胞毒性药物的频繁组成性耐药有关。因此，我们研究了异质性的化疗敏感性转移性皮肤黑色素瘤标本使用离体ATP为基础的化疗敏感性测定（ATP-TCA）。在三个独立的实验室中使用ATP-TCA测试皮肤或淋巴结中的黑色素瘤沉积物（n=55）。对所收集数据的分析（基于任意敏感性指数< 300）显示了相当大的化学敏感性异质性。试验中最具活性的单一细胞毒性剂被鉴定为顺铂、曲奥舒凡、紫杉醇、长春碱、吉西他滨和米托蒽醌。干扰素-α 2b对黑色素瘤细胞生长的直接抑制也有限，尽管已知该药剂具有许多间接生物抗肿瘤作用。将肿瘤细胞暴露于作为单一药剂测试的浓度的药物组合显示，最有效的组合是曲硫凡+吉西他滨、顺铂+紫杉醇和长春碱+紫杉醇。化疗敏感性存在相当大的异质性：一些肿瘤对一种药物或组合反应良好，而另一些肿瘤对此没有反应，而是对测试的替代品之一有反应。偶尔高度耐药的肿瘤显示对测试的任何单一药剂或组合没有反应。观察到的异质性程度表明，ATP-TCA可用于选择可能受益于特定化疗药物单独或联合治疗的患者，这为未来ATP-TCA导向化疗与医生选择的随机对照试验提供了依据，以确定检测导向化疗是否可以改善患者的反应和生存率。[(C)1999 Lippincott威廉姆斯& Wilkins.]。
Advanced melanoma has a poor prognosis and chemotherapy provides little benefit for most patients. This may be related to heterogeneity of chemosensitivity as well as frequent constitutive resistance to individual cytotoxic drugs. We have therefore examined the heterogeneity of chemosensitivity in metastatic cutaneous melanoma specimens using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node were tested using the ATP-TCA, performed in three separate laboratories. Analysis of the data collected (based on an arbitrary sensitivity index < 300) shows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, paclitaxel, vinblastine, gemcitabine and mitoxantrone, There was also a limited direct inhibition of melanoma cell growth by interferon-alpha 2b, although this agent is known to have a number of indirect biological antitumor effects. Exposure of tumor cells to combinations of drugs at the concentrations tested as single agents showed the most active combinations to be treosulfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There was considerable heterogeneity of chemosensitivity: some tumors responded well to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resistant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA could be used to select patients who might benefit from specific chemotherapeutic agents alone or in combination, This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physician's choice to determine whether assay-directed chemotherapy can improve patient response and survival. [(C) 1999 Lippincott Williams & Wilkins.].