Hepatic Arterial Infusion in the Treatment of Liver Metastases with PEG Liposomes in Combination with Degradable Starch Microspheres (DSM) Increases Tumor 5-FU Concentration. An Animal Study in CC-531 Liver Tumor-bearing Rats

The regional application of cytostatics in liver metastases leads to increased concentrations in the tumor tissue. The effect of flow retardation by temporary occlusion and drug targeting with liposome encapsulation (PEG liposomes) on tumor 5-fluorouracil (5-FU) concentrations was investigated. Materials and Methods: Tumor-bearing rats were submitted to i.v. or intraarterial (i.a.) therapy with liposome-encapsulated or non-encapsulated 5-FU. The i.a. groups were additionally treated with or without Spherex ® degradable starch microspheres (DSM). The tumor 5-FU concentrations were determined by high-performance liquid chromatography (HPLC) as area under the curve (AUC). Results: A comparison with i.v. in administered 5-FU yielded the following increases tumor concentrations: 5- FU-PEG liposomes i.v. 27-fold, 5-FU i.a. 19-fold, 5-FU i.a. + DSM 1760-fold, 5-FU-PEG liposomes i.a. 110-fold, 5-FU-PEG liposomes i.a. + DSM 7665-fold. Conculsion: Liver intratumoral 5-FU concentration increases to >7,500 times that following i.v. administration by a combination of regional administration via the hepatic artery with temporary embolization by DSM and drug targeting by liposome-encapsulated 5-FU. The level of therapeutic agent in tumor tissue is the decisive parameter for successful chemotherapy (1, 2). The response has been shown to double when the tumor drug concentration is increased by a factor of 10 (3). A promising approach is regional chemotherapy with intraarterial (i.a.) administration of the cytostatic agent into the target region. The administration of degradable starch microspheres (DSM) has been shown to slow down the blood flow in the unaffected residual liver in favor of the liver tumor. Moreover, the blood flow rate reduction was accompanied by a concomitant increase of the cytostatic agent tumor contact time (4, 5). An increase of the cytostatic agent concentration was also achieved by using liposomes as a drug carrier (6, 7). Liposome-encapsulated cytostatic agents were shown to be therapeutically more effective in experimental tumors, since they were able to overcome both systemic toxicity and drug resistance (8-10). Furthermore, a number of authors (11-13) including ourselves (14) have shown that liposome- encapsulated cytostatic agents change the pharmacokinetic behavior and accumulation of the active substance in the tumor and influence the dose-limiting toxicity.