A comparative study of isolated liver perfusion versus hepatic artery infusion with mitomycin C in rats

A Marinelli,Pjk Kuppen,Amm Eggermont,Cjh Van De Velde,Hcm Franken,Jhm Souverijn

doi:10.1038/bjc.1990.404

Abstract

Systemic toxicity is usually the dose-limiting factor in cancer chemotherapy. Regional chemotherapy is therefore an attractive strategy in the treatment of liver metastasis. Two ways of regional chemotherapy, hepatic artery infusion (HAI) and isolated liver perfusion (ILP), were compared investigating the difference in toxicity with tissue and biofluid concentrations of mitomycin C (MMC). In wistar derived WAG rats the maximally tolerated dose of mitomycin C via HAI was 1.2 mg kg-1. Body weight measurements after HAI with doses higher than 1.2 mg kg-1 suggest both an acute and delayed toxic effect of mitomycin C since the time weight curves were triphasic: a rapid weight loss, a steady state and a second fall in weight phase. These rats died due to systemic toxicity. ILP with 4.8 mg kg-1 was associated with no signs of systemic toxicity and only transient mild hepatotoxicity. ILP with 6.0 mg kg-1 was fatal mainly due to hepatic toxicity. The four times higher maximally tolerated dose in ILP resulted in a 4-5 times higher peak concentration of mitomycin C in liver tissue, while the plasma concentration remained significantly lower than in the HAI treated rats. In the tumour tissue a 500% higher concentration of mitomycin C was measured in the ILP with 4.8 mg kg-1 than in HAI with 1.2 mg kg-1 treated rats. We demonstrated that when mitomycin C was administered by ILP a 400% higher dose could be safely administered and resulted in a five times higher tumour tissue concentration. In view of the steep dose-response curve of this alkylating agent this opens new perspectives for the treatment of liver metastasis.

Highlights

In the majority (75%) of the patients with colorectal cancer metastases confined to the liver, the tumour is not resectable
Control hepatic artery infusion (HAI) with saline 0.9% had no effect on body weight
When intermediate doses (1.5 and 2.4mg kg-') were administered the time-weight change curves were characterised by a triphasic pattern: a rapid weight loss, a steady state and a second fall in weight phase (Figure la)

Summary

Introduction

In the majority (75%) of the patients with colorectal cancer metastases confined to the liver, the tumour is not resectable. These patients are eligible for locoregional therapies. The rationale of regional administration of chemotherapy is based on the concept of achieving a high local concentration, while minimising systemic drug levels and, reducing dose limiting systemic side-effects (Collins, 1984). For most chemotherapeutic agents steep dose-response curves can be demonstrated. High drug concentrations are important for both sensitive and resistant tumour cells. For resistant cells extremely high exposure is required for adequate cell kill (Slee et al, 1987; Kuppen et al, 1988)

Results

Discussion

Conclusion