Department of Surgery, Shaare Zedek Medical Center and Hebrew University-Faculty of Medicine, Jerusalem, Israel.
Department of Pathology, Shaare Zedek Medical Center and Hebrew University-Faculty of Medicine, Jerusalem, Israel.
Cancer Chemother Pharmacol. 2022 Aug;90(2):109-114. doi: 10.1007/s00280-022-04451-1. Epub 2022 Jul 8.
To examine the ex- vivo ability of explanted human tumors and normal tissue to activate liposomal mitomycin C lipidic prodrug (MLP) by releasing the active free drug form, mitomycin C (MMC).
We tested conversion of MLP to MMC in an ex vivo assay using explanted tissues obtained during routine surgery to remove primary tumors or metastases. Tumor and adjacent normal tissue were obtained from freshly explanted tumors and were immediately deep frozen at - 70 °C. On test day, the fragments were thawed, homogenized and incubated in the presence of a fixed amount of liposomal MLP at 37 °C for 1 h. We measured MLP and its rate of conversion to MMC by HPLC. Controls included plasma, malignant effusions, red blood cells, tumor cell lines, mouse liver, and buffer with dithiothreitol, a potent reducing agent.
Most patients tested (16/20) were diagnosed with colo-rectal carcinoma. The average fraction of MLP cleaved per 100-mg tumor tissue (21.1%, SEM = 1.8) was greater than per 100-mg normal tissue (16.6%, SEM = 1.3). When the tumor and normal tissue samples were paired by patient, the difference was statistically significant (p = 0.022, paired t test). Biological fluids did not activate liposomal MLP, while normal liver tissue strongly does. Interestingly, the omental fatty tissue also greatly activated MLP.
Tumor tissue homogenates activate MLP with greater efficiency than the surrounding normal tissues, but far less than liver and adipose tissue. These observations demonstrate the bioavailability of liposomal MLP in human tumors, and its pharmacologic potential in cancer therapy.
研究从原发性肿瘤或转移灶切除手术中获得的离体人肿瘤和正常组织释放游离药物米托蒽醌（MMC）的能力，以评估其激活脂质体丝裂霉素 C 前药（MLP）的能力。
我们采用离体组织检测法，在离体实验中检测 MLP 向 MMC 的转化。组织标本来自于新鲜离体肿瘤，迅速在 -70°C 深低温冻存。在检测日，将组织标本融化，匀浆并在 37°C 下与固定浓度的脂质体 MLP 孵育 1 小时。采用 HPLC 法检测 MLP 及其向 MMC 的转化速率。对照组包括血浆、恶性渗出液、红细胞、肿瘤细胞系、鼠肝及含二硫苏糖醇（一种强效还原剂）的缓冲液。
大多数患者（16/20）诊断为结直肠癌。100mg 肿瘤组织（21.1%，SEM=1.8）裂解的 MLP 比例大于 100mg 正常组织（16.6%，SEM=1.3）。当按患者对肿瘤和正常组织样本进行配对时，差异具有统计学意义（p=0.022，配对 t 检验）。生物体液不会激活脂质体 MLP，而正常肝组织则会强烈激活它。有趣的是，大网膜脂肪组织也大大激活了 MLP。
肿瘤组织匀浆比周围正常组织更有效地激活 MLP，但远低于肝和脂肪组织。这些观察结果表明，脂质体 MLP 在人肿瘤中的生物利用度及其在癌症治疗中的药理潜力。
