Ajani Jaffer A, Jiang Yixing, Faust Josephine, Chang Baochong B, Ho Linus, Yao James C, Rousey Steven, Dakhil Shaker, Cherny Richard C, Craig Catherine, Bleyer Archie
Department of GI Medical Oncology, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Invest New Drugs. 2006 Jul;24(4):353-7. doi: 10.1007/s10637-006-6452-1.
Protein Kinase C (PKC), involved in transmembrane signaling of cell surface receptors, promotes carcinogenesis and tumor progression. Bryostatin-1 competes with PKC for phorbol esters (tumor promoters), thus inhibiting tumor progression. Bryostatin-1 also increases cytotoxicity of paclitaxel in a sequential fashion. We studied sequential paclitaxel and bryostatin-1 in patients with untreated, advanced gastric adenocarcinoma.
Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with advanced, measurable cancers were eligible. Patients were required to have near normal organ function and ECOG performance status of 0 or 1. All patients gave an informed consent. Patients received paclitaxel 80 mg/m2 in 2 h intravenously on day 1 and bryostatin-1 40 mcg/m2 in 1 h intravenously on day 2 each week for 3 consecutive weeks out of 4. Primary objective was to assess the objective response rate.
In a multi-center setting, 37 patients were enrolled and 35 were assessable for response. A confirmed partial response rate was 29%. The median time-to-progression was 4.25 months and the median survival time was 8 months. Grade 3 cumulative myalgias occurred in 55% of patients. Twelve patients discontinued therapy due to myalgias, including 6 patients who had not progressed after achieving a partial response. Other toxic effects were uncommon.
Sequential paclitaxel plus bryostatin-1 resulted in a superior response rate than would be expected of paclitaxel alone in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Further development of this combination is warranted once an effective method to ameliorate or prevent myalgias can be established.
蛋白激酶C（PKC）参与细胞表面受体的跨膜信号传导，促进癌症发生和肿瘤进展。苔藓抑素-1与PKC竞争佛波酯（肿瘤促进剂），从而抑制肿瘤进展。苔藓抑素-1还以序贯方式增加紫杉醇的细胞毒性。我们研究了序贯使用紫杉醇和苔藓抑素-1治疗未经治疗的晚期胃腺癌患者的情况。
经组织学证实为胃或胃食管交界腺癌且癌症晚期、可测量的患者符合条件。患者需器官功能接近正常，东部肿瘤协作组（ECOG）体能状态为0或1。所有患者均签署知情同意书。患者在第1天静脉滴注2小时紫杉醇80mg/m²，在第2天静脉滴注1小时苔藓抑素-1 40μg/m²，每周一次，连续4周中的3周。主要目的是评估客观缓解率。
在多中心研究中，共纳入37例患者，其中35例可评估疗效。确认的部分缓解率为29%。中位疾病进展时间为4.25个月，中位生存时间为8个月。55%的患者出现3级累积性肌痛。12例患者因肌痛停止治疗，其中6例在达到部分缓解后病情未进展。其他毒性作用不常见。
对于未经治疗的晚期胃或胃食管交界腺癌患者，序贯使用紫杉醇加苔藓抑素-1的缓解率优于单独使用紫杉醇预期的缓解率。一旦能建立有效改善或预防肌痛的方法，该联合方案值得进一步研发。
