Schrump David S, Fischette Maria R, Nguyen Dao M, Zhao Ming, Li Xinmin, Kunst Tricia F, Hancox Ana, Hong Julie A, Chen G Aaron, Kruchin Evgeny, Wright John J, Rosing Douglas R, Sparreboom Alex, Figg William D, Steinberg Seth M
Thoracic Oncology Section Surgery Branch, Center for Cancer Research and Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Clin Cancer Res. 2008 Jan 1;14(1):188-98. doi: 10.1158/1078-0432.CCR-07-0135.
Our preclinical experiments indicated that Romidepsin (Depsipeptide FK228; DP) mediates growth arrest and apoptosis in cultured lung cancer cells. A phase II trial was done to examine clinical and molecular responses mediated by this histone deacetylase inhibitor in lung cancer patients.
Nineteen patients with neoplasms refractory to standard therapy received 4-h DP infusions (17.8 mg/m(2)) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of two identical 21-day cycles. Plasma DP levels were evaluated by liquid chromatography-mass spectrometry techniques. A variety of molecular end points were assessed in tumor biopsies via immunohistochemistry techniques. Long oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after DP exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections.
Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in one individual. No significant cardiac toxicities were observed. Maximum steady-state plasma DP concentrations ranged from 384 to 1,114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in nine patients. DP enhanced acetylation of histone H4, increased p21 expression in lung cancer cells, and seemed to shift global gene expression profiles in these cells toward those detected in normal bronchial epithelia.
Although exhibiting minimal clinical efficacy at this dose and schedule, DP mediates biological effects that may warrant further evaluation of this histone deacetylase inhibitor in combination with novel-targeted agents in lung cancer patients.
我们的临床前实验表明，罗米地辛（缩肽FK228；DP）可介导培养的肺癌细胞生长停滞和凋亡。开展了一项II期试验，以研究这种组蛋白脱乙酰酶抑制剂在肺癌患者中介导的临床和分子反应。
19例对标准治疗难治的肿瘤患者在21天周期的第1天和第7天接受4小时的DP静脉输注（17.8mg/m²）。每个完整疗程由两个相同的21天周期组成。采用液相色谱-质谱技术评估血浆DP水平。通过免疫组织化学技术在肿瘤活检中评估多种分子终点。使用长寡核苷酸阵列检测DP暴露前后激光捕获的肿瘤细胞中的基因表达谱，相对于接受肺切除术患者的肺癌细胞和相邻正常支气管上皮细胞。
19例患者可进行毒性评估；18例可进行治疗反应评估。1例患者出现剂量限制性骨髓抑制。未观察到明显的心脏毒性。最大稳态血浆DP浓度范围为384至1114ng/mL。未观察到客观反应。9例患者疾病出现短暂稳定。DP增强了组蛋白H4的乙酰化，增加了肺癌细胞中p21的表达，并似乎使这些细胞的整体基因表达谱向正常支气管上皮细胞中检测到的谱型转变。
尽管在此剂量和方案下临床疗效甚微，但DP介导的生物学效应可能值得进一步评估这种组蛋白脱乙酰酶抑制剂与新型靶向药物联合用于肺癌患者。
