Hydralazine与valproate（丙戊酸盐）显然可以克服化疗抗药性

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Hydralazine与valproate（丙戊酸盐）显然可以克服化疗抗药性

合併两种常用药物：hydralazine与magnesium valproate，显然可以克服化疗抗药性。一项发表於9月号肿瘤学科学誌中的第二期世代研究结果显示，这样的药物合併疗法对15位病患中的12位（80%）有临床好处；这些病患罹患各种不同癌症，且儘管接受化学治疗，疾病仍然进展中；在使用过hydralazine与valproate治疗后，重新使用一样的化学治疗后，4位病患出现部份反应，而8位病患疾病稳定下来。
　　
　　这样的合併疗法被认為透过逆转导致化学疗法抗药性的表观基因脱序：hydralazine，是一种早期的降血压药物，也可以作為DNA甲基化的抑制剂，然而，抗癲癇药物magnesium valproate是组织蛋白去乙醯化的一种抑制剂。
　　
　　主要作者墨西哥Tlapan市国家癌症机构Alfonso Duenas-Gonzalez医师向Medscape表示，这些结果非常清楚地显示，甲基化与组织蛋白乙醯化会某个程度上地消除表观基因标记，造成化学治疗的抗药性，已经於多次的实验模式中获得证实；他的团队目前正在进行两项随机分派第三期临床试验，使用hydralazine与valproate，他表示，墨西哥卫生当局目前正在审查这样的合併疗法（可能以Transkrip的商品名上市），使用於对治疗反应不佳的固体肿瘤病患身上。
　　
　　身為一个肿瘤学家，他表示，使用这样的合併疗法於没有其他治疗选择且已经与病患有过深入讨论的治疗反应不佳病患，是值得考虑的；他的评论是，这样的建议是基於此两种药物的安全性良好；然而，他附带表示，只有在第三期临床研究完成后，我们才知道这样的治疗在癌症疗法上的地位。
　　
　　在文章随后的评论中，提到这样的结果是相当刺激的，但主编认為这项结果应该谨慎阐释，因為不同的肿瘤与化学治疗之间差异很大，接受第一週的hydralazine与magnesium valproate治疗就进展的病患，被排除於试验之外；主编英国伦敦Imperial大学Robert Brown博士以及苏格兰格拉斯哥彼得森西苏格兰癌症中心Rosalind Glasspool医师指出，不管如何，以一种相对耐受性良好的治疗就可以逆转化学治疗抗药性是很弔诡的，且这样的表观基因治疗正在进行许多临床研究中。
　　
　　【肿瘤与化学治疗时程的差异】
　　目前这项第二期临床试验中，研究者表示27位病患签署受试者同意书，但其中3位不符合研究收纳标準，且并未使用hydralazine与valproate，然而，另外7位病患在第一週、第一次投予药物前就因為疾病进展放弃治疗；更有2位病患在试验计划中完成两个週期的化学治疗，但是无法评估的，因為无法确认疾病进展是否发生於他们纳入计画之前；这2位病患纳入最后评估毒性的17位患者中，但并未收纳到评估疗效的15位患者中。
　　
　　收纳病患的癌症包括卵巢（7位病患）、子宫颈（3位）、乳癌（3位）、肺癌（1位）、与睪丸癌（1位），而使用的化学治疗包括cisplatin、carboplatin、paclitaxel、vinorelbine、gemcitabine、pemetrexed、topotecan、doxorubicin、cyclophosphamide与anstrazole；所有病患至少接受两个週期的化学治疗，且在第二个或是第三个化学治疗疗程间进展；确认疾病进展后的30天内开始计划治疗，在下一次化学治疗前一个星期进行；快速乙醯者接受182 mg的hydralazine、缓慢乙醯者接受83 mg的hydralazine，而magnesium valproate的使用剂量為40 mg/kg。
　　
　　研究者表示，这项研究的设计是独特的，大部分的病患在化学治疗下疾病仍然进展，这样的现象可以以有7位病患在第一次化学治疗週期前，正在接受hydralazine与valproate的那个星期进展表现，因此，达到治疗反应与稳定疾病可以仅归功於表观基因治疗，因為这是试验前与计画中疗程唯一有差异的地方。
　　
　　Duenas-Gonzalez博士向Medscape表示，他的团队也已经针对乳癌及子宫颈癌患者进行研究，结果显示表观基因治疗能够增加大约1000种与压抑肿瘤有关基因的表现，这样的成果是在8天的hydralazine与valproate治疗后以微阵列分析原发性肿瘤而来；除此之外，他表示，另一个来自美国Lee Moffitt癌症中心的研究团队，最近报告了一项针对过去接受重度治疗的固体肿瘤患者，在epirubicin治疗之前使用valproic acid的研究（Munster P等人，J Clin Oncol 2007;25:1979-1985）；他们报告9位（22%）罹患不同癌症的患者有部份反应、16位患者达到疾病稳定或些微反应（39%），虽然这项研究中未使用hydralazine作為去甲基化药物。
　　
　　Duenas-Gonzalez博士指出，墨西哥团队目前正在进行两项第三期临床研究，一项是针对143位持续性、再发性、或转移性子宫颈癌症病患，将其随机分派接受cisplatin与topotecan，加上或未加上hydralazine与valproate；另外一项将会针对211位对cisplatin產生抗药性的卵巢癌患者，将其随机分派到仅接受topotecan或加上hydralazine及valproate；在这两项研究中，试验终点都是疾病未进展的存活率。

Hydralazine and Valproate Appear to Overcome Resistance to Chemotherapy

The combination of 2 commonly used drugs, hydralazine and magnesium valproate, appears to overcome resistance to chemotherapy. A single-cohort phase 2 study, reported in the September issue of the Annals of Oncology, found that the drug combination led to clinical benefit in 12 of 15 patients (80%). These patients had various tumors and were actively progressing despite chemotherapy. After a course of hydralazine and valproate, rechallenge with the same chemotherapy produced partial response in 4 patients and disease stabilization in 8 patients.

The combination is thought to work by reversing epigenetic aberrations that lead to chemotherapy resistance: hydralazine, an early antihypertensive agent, acts as an inhibitor of DNA methylation, while the antiepileptic magnesium valproate is an inhibitor of histone deacetylation.

\"These results are very clearly suggestive that demethylation and histone acetylation somehow erased the epigenetic mark, leading to chemotherapy resistance, as has been shown in a multiplicity of experimental models,\" lead author Alfonso Dueñas-González, MD, from the Instituto Nacional de Cancerología, in Tlapan, Mexico, tells Medscape. His group is now conducting 2 randomized phase 3 clinical trials of hydralazine and valproate, and he notes that the Mexican health authorities are currently reviewing use of this combination (under the potential trade name Transkrip) for approval in refractory patients with solid tumors. As an oncologist, he says it is worth considering a trial of the combination in refractory patients for whom no other therapeutic option exists and after extensive discussion with the patient. \"This suggestion is based on the very well-known safety of these drugs,\" he comments. However, he adds, \"It is clear that only when phase 3 clinical trials are completed will we know its place in the cancer therapy armamentarium.\"

An accompanying editorial says the results \"are certainly provocative\" but adds that they should be \"interpreted with caution\" because of the heterogeneity of the tumor types and chemotherapy regimens and because patients who showed early progression during the first week of therapy with hydralazine and magnesium valproate were excluded. \"Nevertheless, it is intriguing that reversal of resistance might be possible with a relatively well-tolerated treatment, and this is a concept that is being tested in a number of ongoing trials of epigenetic therapies,\" write the editorialists, Robert Brown, PhD, from Imperial College, in London, United Kingdom, and Rosalind Glasspool, MD, from the Beatson West of Scotland Cancer Center, in Glasgow, Scotland.

Variety of Tumors and Chemotherapy Schedules

For the current phase 2 study, the researchers explain that 27 patients signed informed-consent documents, but 3 were ineligible and did not initiate hydralazine and valproate, while 7 patients abandoned the study during the first week of this therapy, before the first administration of chemotherapy, due to clinical deterioration. A further 2 patients completed 2 chemotherapy cycles in the study protocol but were unevaluable because progression before their inclusion in the protocol could not be confirmed. These 2 patients were included in the 17 that were evaluable for toxicity, but not in the 15 patients evaluable for response.

The range of cancers included ovarian (7 patients), cervix (3), breast (3), lung (1), and testis (1), and chemotherapy schedules included cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. All patients had received at least 2 courses of chemotherapy and showed progressive disease at the second or third chemotherapy course. Protocol therapy started within 30 days after progression was confirmed, beginning a week before chemotherapy was restarted. Hydralazine was given at a dose of 182 mg for rapid acetylators and 83 mg for slow acetylators, and magnesium valproate at a dose of 40 mg/kg.

\"This study design is unique in that the majority of patients were actively progressing on chemotherapy,\" say the researchers. \"This is best illustrated by the fact that 7 patients deteriorated clinically during the week of hydralazine and valproate administration and prior to the first chemotherapy cycle. Therefore, the achievement of response and disease stabilization can be attributed only to the use of the epigenetic agents, because this was the only difference between prestudy and protocol regimens.\"

Dr. Dueñas-González told Medscape that his group has also conducted previous studies in breast cancer and cervical cancer that show that epigenetic drugs are able to upregulate about 1000 genes implicated in tumor suppression, as shown by microarray analysis in the primary tumors after 8 days of hydralazine and valproate therapy. Also, he notes that a separate group of researchers, from the Lee Moffitt Cancer Center in the United States, has recently reported a phase 1/2 study of valproic acid prior to epirubicin in heavily pretreated solid-tumor patients (Münster P et al. J Clin Oncol 2007;25:1979-1985). They reported partial responses across different tumor types in 9 patients (22%) and stable disease/minor responses in 16 patients (39%), although they did not use hydralazine as a demethylating agent.

The Mexican team is now conducting 2 phase 3 trials, Dueñas-González said. One will involve 143 cervical cancer patients with persistent, recurrent, or metastatic disease, randomized to receive cisplatin and topotecan with or without hydralazine and valproate. The other will be conducted in 211 cisplatin-resistant ovarian cancer patients randomized to single-agent topotecan with or without hydralazine and valproate. In both studies, the end point will be progression-free survival.