Chemosensitisation of malignant melanoma by BCL2 antisense therapy
Chemosensitisation of malignant melanoma by BCL2 antisense therapy
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DOI：
10.1016/s0140-6736(00)03207-4
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发表时间：
2000-11-18
期刊：
影响因子：
168.9
通讯作者：
Pehamberger, H
中科院分区：
文献类型：
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作者：
Jansen, B;Wacheck, V;Pehamberger, H
恶性黑色素瘤的化疗耐药性与原癌基因BCL 2的表达有关。针对BCL 2 mRNA的反义寡核苷酸（阿索）降低BCL 2蛋白浓度，增加肿瘤细胞凋亡，并在小鼠异种移植模型中与全身性达卡巴嗪联合使用时导致肿瘤反应。这项I-II期临床研究调查了BCL 2阿索与人源性前列腺素B1受体拮抗剂（P53）的组合。（augmerosen，Genasense，G3139）和达卡巴嗪治疗BCL 2表达的晚期恶性黑色素瘤患者的疗效。对14例晚期恶性黑色素瘤患者静脉或皮下给予奥格美生，每日剂量为0.6- 6.5mg/kg，同时给予标准达卡巴嗪治疗（总剂量高达1000 mg/m2/周期）。根据常见毒性标准对毒性进行评分。通过高效液相色谱法测定血浆奥格美森浓度。在一系列肿瘤活检样本中，BCL 2蛋白浓度测定蛋白质印迹法和肿瘤细胞凋亡assessed.Findings的联合方案耐受性良好，没有剂量限制性毒性。血液学异常为轻度至中度。淋巴细胞减少症常见，但未发生发热性中性粒细胞减少症。较高剂量的奥格美生与一过性发热有关。4例患者肝功能异常，1周内消退。在24小时内达到稳态血浆浓度，并随给药剂量增加而增加。到第5天，与基线相比，1.7 mg/kg及更高的日剂量导致黑色素瘤样本中的BCL 2蛋白中位数降低40%，同时肿瘤细胞凋亡增加，达卡巴嗪治疗后肿瘤细胞凋亡大大增加。6例患者显示出抗肿瘤反应（1例完全，2例部分，3例轻微）。所有患者的估计中位生存期现在超过12个月。解释全身施用奥格美生下调转移性癌症中的靶BCL 2蛋白。BCL 2的这种下调与标准抗癌疗法相结合，为治疗耐药肿瘤患者提供了一种新的方法。
Background Chemoresistance of malignant melanoma has been linked to expression of the proto-oncogene BCL2. Antisense oligonucleotides (ASO) targeted against BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-cell apoptosis, and led to tumour responses in a mouse xenotransplantation model when combined with systemic dacarbazine. This phase I-II clinical study investigated the combination of BCL2 ASO (augmerosen, Genasense, G3139) and dacarbazine in patients with advanced malignant melanoma expressing BCL2.Methods In a within-patient dose-escalation protocol, 14 patients with advanced malignant melanoma were given augmerosen intravenously or subcutaneously in daily doses of 0.6-6.5 mg/kg plus standard dacarbazine treatment (total doses up to 1000 mg/m(2) per cycle). Toxicity was scored by common toxicity criteria. Plasma augmerosen concentrations were assayed by high-performance liquid chromatography. In serial tumour biopsy samples, BCL2 protein concentrations were measured by western blotting and tumour-cell apoptosis was assessed.Findings The combination regimen was well tolerated, with no dose-limiting toxicity. Haematological abnormalities were mild to moderate. Lymphopenia was common, but no febrile neutropenia occurred. Higher doses of augmerosen were associated with transient fever. Four patients had liver-function abnormalities that resolved within 1 week. Steady-state plasma concentrations of augmerosen were attained within 24 h, and increased with administered dose. By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrease in BCL2 protein in melanoma samples compared with baseline, concomitantly with increased tumour-cell apoptosis, which was greatly increased after dacarbazine treatment. Six patients have shown antitumour responses (one complete, two partial, three minor). The estimated median survival of ail patients now exceeds 12 months.Interpretation Systemic administration of augmerosen downregulated the target BCL2 protein in metastatic cancer. Such downregulation of BCL2, combined with standard anticancer therapy, offers a new approach to the treatment of patients with resistant neoplasms.