Smith J P, Kanekal S, Patawaran M B, Chen J Y, Jones R E, Orenberg E K, Yu N Y
Department of Medicine, Division of Gastroenterology, The Milton S. Hershey Medical Center, The Pennsylvania State University, P.O. Box 850, Hershey, PA 17033, USA.
Cancer Chemother Pharmacol. 1999;44(4):267-74. doi: 10.1007/s002800050977.
Pancreatic cancer is widespread, associated with high mortality, and rapidly fatal. Most cases are diagnosed too late for surgical treatment, and the disease responds poorly to systemic chemotherapy. Nevertheless, pancreatic cancer cells are sensitive to fluorouracil (5-FU) in a time- and dose-dependent manner, suggesting that improved retention of drug in the tumor may improve patient prognosis. In this study, we evaluated a novel drug delivery system, 5-FU/epinephrine injectable gel (5-FU/epi gel), designed to improve drug retention in tumors.
We used a BxPC-3 human pancreatic cancer xenograft model in athymic mice to examine drug levels in tumor, liver, and kidney tissue following administration of: (a) 5-FU/epi gel (30 mg 5-FU/ml) intratumorally (i.t.); (b) 5-FU solution i.t.; and (c) 5-FU solution intraperitoneally (i.p.). [(3)H]5-FU was added as a radiolabeled marker to all test formulations. Animals were sacrificed at designated times, and the tumor, liver, and one kidney from each animal were excised and processed for radioactivity analysis. Drug concentration was quantified by both storage-phosphor autoradiography (SPA) and liquid scintillation counting (LSC).
Higher and sustained i.t. drug levels were achieved following i.t. administration of 5-FU/epi gel (SPA AUC 18.4 mM. h, LSC AUC 13.0 mM. h) compared with 5-FU solution i.t. (SPA AUC 2.02 mM. h, LSC AUC 1.92 mM. h) or 5-FU solution i.p. (SPA AUC 0.07 mM. h, LSC AUC 0.04 mM. h). Use of the 5-FU/gel system was associated with lower drug levels in liver and kidney, indicating that it produces far less systemic exposure.
In the human pancreatic cancer xenografts, i.t. administration of 5-FU/epi injectable gel provided significantly higher drug and/or metabolite concentrations for extended periods than was possible with either i.t. or i.p administration of drug solution. This i.t. drug delivery system could potentially be used to treat patients with pancreatic cancer to increase tumor exposure to drug and improve the therapeutic index in comparison to systemic drug administration.
胰腺癌广泛存在，死亡率高，且进展迅速。大多数病例在确诊时已错过手术治疗时机，且该疾病对全身化疗反应不佳。然而，胰腺癌细胞对氟尿嘧啶（5-FU）具有时间和剂量依赖性敏感性，这表明提高药物在肿瘤中的滞留时间可能改善患者预后。在本研究中，我们评估了一种新型药物递送系统，即5-FU/肾上腺素可注射凝胶（5-FU/epi凝胶），旨在提高药物在肿瘤中的滞留率。
我们在无胸腺小鼠中使用BxPC-3人胰腺癌异种移植模型，以检测在给予以下药物后肿瘤、肝脏和肾脏组织中的药物水平：（a）瘤内注射（i.t.）5-FU/epi凝胶（30mg 5-FU/ml）；（b）瘤内注射5-FU溶液；（c）腹腔注射（i.p.）5-FU溶液。将[³H]5-FU作为放射性标记物添加到所有测试制剂中。在指定时间处死动物，切除每只动物的肿瘤、肝脏和一个肾脏，并进行放射性分析。通过存储磷光体放射自显影（SPA）和液体闪烁计数（LSC）对药物浓度进行定量。
与瘤内注射5-FU溶液（SPA AUC 2.02 mM·h，LSC AUC 1.92 mM·h）或腹腔注射5-FU溶液（SPA AUC 0.07 mM·h，LSC AUC 0.04 mM·h）相比，瘤内注射5-FU/epi凝胶后可实现更高且持续的瘤内药物水平（SPA AUC 18.4 mM·h，LSC AUC 13.0 mM·h）。使用5-FU/凝胶系统时肝脏和肾脏中的药物水平较低，表明其产生的全身暴露要少得多。
在人胰腺癌异种移植模型中，与瘤内或腹腔注射药物溶液相比，瘤内注射5-FU/epi可注射凝胶在较长时间内提供显著更高的药物和/或代谢物浓度。这种瘤内药物递送系统可能潜在地用于治疗胰腺癌患者，以增加肿瘤对药物的暴露并与全身给药相比提高治疗指数。
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