Director of Pharmaceutical Research, Delcath Systems, Inc., 566 Queensbury Avenue, Queensbury, NY 12804, USA.
Anticancer Res. 2013 May;33(5):1989-2000.
The goal of this study was to determine whether liver, gastric, or colonic cancer may be suitable targets for chemosaturation therapy with percutaneous hepatic perfusion (CS-PHP) and to assess the feasibility of utilizing other cytotoxic agents besides melphalan in the CS-PHP system.
Forty human cell lines were screened against three cytotoxic chemotherapeutic agents. Specifically, the dose-dependent effect of melphalan, oxaliplatin, and paclitaxel on proliferation and apoptosis in each cell line was evaluated. These agents were also evaluated for their ability to induce apoptosis in normal primary human hepatocytes. A high-dose short-term drug exposure protocol was employed to simulate conditions encountered during CS-PHP.
The average concentration of melphalan required for inducing significant apoptosis was 61 μM, or about 3-fold less than the theoretical concentration of 192 μM, achieved in the hepatic artery during CS-PHP dosing with melphalan. Additionally, we found that gastric cancer cell lines were 2-5 fold more sensitive to apoptosis than liver cancer cell lines to all three compounds, suggesting that in addition to colonic and gastric cancer metastases to the liver, primary gastric cancer may also be amenable to management by CS-PHP using an appropriate therapeutic agent. Significantly, at concentrations that are predicted using the CS-PHP system, these agents caused apoptosis of colonic, gastric, and liver cancer cells but were not toxic to primary human hepatocytes.
The compounds tested are potential candidates for use in the CS-PHP system to treat patients with gastric and colonic metastases, and primary cancer of the liver.
本研究旨在确定肝、胃或结直肠癌是否可能成为经皮肝灌注化疗（CS-PHP）化学饱和治疗的靶标，并评估除美法仑以外的其他细胞毒性药物在 CS-PHP 系统中的应用可行性。
筛选了 40 个人类细胞系，以对抗三种细胞毒性化疗药物。具体而言，评估了美法仑、奥沙利铂和紫杉醇对每种细胞系增殖和凋亡的剂量依赖性作用。还评估了这些药物在诱导正常原代人肝细胞凋亡方面的能力。采用高剂量短期药物暴露方案模拟 CS-PHP 过程中遇到的条件。
诱导明显凋亡所需的美法仑平均浓度为 61μM，约为 CS-PHP 美法仑给药时肝动脉中理论浓度 192μM 的 3 倍。此外，我们发现与肝癌细胞系相比，胃癌细胞系对三种化合物的凋亡更为敏感，敏感性提高了 2-5 倍，这表明除了结直肠和胃癌转移到肝脏外，原发性胃癌也可能通过 CS-PHP 用适当的治疗药物进行治疗。重要的是，在 CS-PHP 系统中预测的浓度下，这些药物可诱导结直肠、胃癌和肝癌细胞凋亡，但对原代人肝细胞没有毒性。
所测试的化合物可能是 CS-PHP 系统治疗胃和结直肠转移及原发性肝癌患者的潜在候选药物。
