Effectiveness of isolated liver perfusion with mitomycin C in the treatment of liver tumours of rat colorectal cancer

Abstract

Summary Dose limiting systemic toxicity prevents sufficient exploitation of the steep dose response relationship of most anticancer agents. In our rat liver tumour model (the CC531 colorectal carcinoma), isolated liver perfusion allows administration of higher doses of mitomycin C than hepatic artery infusion, while systemic toxicity remains minimal. To determine the temporal pattern of mitomycin C induced cytokinetic changes, we analysed flow cytometric DNA histograms of CC53 1 liver tumours from rats treated with high dose mitomycin C (3.2 mg kg-') via hepatic artery infusion and sacrificed at different time intervals after treatment. Between 12 and 36 h after treatment, the fraction of cells in late S and G2/M phase had markedly increased. The effects of administration of the respective maximally tolerated doses of mitomycin C in isolated liver perfusion and via hepatic artery infusion on progression of tumour cells through the cell cycle and on gross tumour growth were compared. Isolated liver perfusion with mitomycin C resulted in a significant increase in the proportion of cells in mid and late S, and in some accumulation of cells in early S and G2/M phase at 24 and 48 h after treatment. In contrast, after hepatic artery infusion a significant increase of the fraction of cells in G2/M phase was observed at 24 h after treatment. Monitoring tumour growth after isolated liver perfusion five out of seven rats showed a complete tumour remission, while after hepatic artery infusion only a minimal growth delay was detected. This study demonstrates that isolated liver perfusion in the rat CC531 liver tumour model allows the administration of a well-tolerated dose of mitomycin C being high enough to induce a marked DNA synthesis inhibition and even complete tumour remission.Colorectal cancer is one of the most common malignant tumours (Silverberg & Lubera, 1987). The liver is the major site of metastatic spread and in 40% of the patients also the sole site of initial recurrence (Cohen et al., 1989, pp. 906

Intra-hepatic Mitomycin C bolus infusion in the treatment of extensive liver metastases of breast cancer

“…However, MMC is an excellent candidate for regional administration because of the high first pass hepatic extraction that assures high local drug concentrations with a reduced systemic toxicity [18,19]. In a rat model of liver metastases from colorectal cancer, isolated liver perfusion with MMC induced a marked DNA synthesis inhibition and even complete tumour remission [20]. MMC has been used intra-arterially as regional chemotherapy for metastatic colorectal cancer and has given good responses [15,17].…”

Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion

“…Re-absorption of the 1979; Millar et al, 1986;Bates & Mackillop, 1990) ILP with mitomycin C also resulted in complete remissions in rats (Marinelli et al, 1991). The technique of isolated liver perfusion has been already extensively and successfully tested in patients by different groups (Aigner et al, 1988;Hafstr6m et al, 1990) without serious (post-) operative complications.…”

“…Although ILP with 5-fluorouracil (FUra) and mitomycin C (MMC) has recently been applied in patients by Aigner et al (1988), data on the effectiveness of this approach are not yet available. In experimental studies in rats, the effectiveness of ILP has been reported for FUra (Radnell et al, 1990;Marinelli et al, 1990b) and MMC (Marinelli et al, 1991). Only with MMC complete remissions and a significantly prolonged survival has been reported (Marinelli et al, 1991).…”

“…In experimental studies in rats, the effectiveness of ILP has been reported for FUra (Radnell et al, 1990;Marinelli et al, 1990b) and MMC (Marinelli et al, 1991). Only with MMC complete remissions and a significantly prolonged survival has been reported (Marinelli et al, 1991). In rats, hepatotoxic side effects of MMC was dose limiting (Marinelli et al, 1990a).…”

Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells

“…Chemotherapy using fluoropyrimidines, often in combination with modulators like leucovorin, methotrexate or interferon, is most often used in these patients, but with a minimal increase in survival rates (Meropol et al, 1995). Hepatic arterial infusion of chemotherapeutics results in higher response rates and survival in preclinical and clinical studies (Marinelli et al, 1991;Kemeny, 1995), indicating that local drug application may offer good prospects.…”