Abstract
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 CC531 liver tumours from rats treated with high dose mitomycin C (3.2 mg kg-1) 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.
Highlights
Since changes in cell cycle progression are a sensitive indicator for the intracellular effects of cytostatic drugs (Gray et al, 1987, pp. 93), we evaluated changes in DNA distributions of mitomycin C treated tumours by flow cytometry
Histograms obtained with tumour cells collected after hepatic artery infusion or isolated liver perfusion without drug (Figures 2b, 3 II and III, respectively) were identical to those obtained from tumours of untreated control rats (Figures 2b and 3 1)
In late S phase no accumulation of cells was seen after treatment with 1.2 mg kg-', while late S was significantly increased after treatment with 3.2 mg kg' (Figures 1, 2a and b)
Summary
The WAG rat tumour cell line CC531 is a dimethyl-hydrazine induced carcinoma of the colon and is weakly immunogenic (Marquet et al, 1984). Cells are maintained in culture in RPMI 1640 (Dutch modification; GIBCO Europe B.V., Breda, The Netherlands), supplemented with 10% foetal calf serum (GIBCO Limited, Paisley, Scotland), 2 mM L-glutamine, 50 ,lg ml-' streptomycin and 50 IU ml penicillin. Male WAG/Ola rats weighing 250-300 g were inoculated with cells from cultures between passages 105-115. The rats underwent laparotomy and 5.105 cells in 0.05ml Hanks Balanced Salt Solution (University Hospital, Leiden, The Netherlands) were subcapsularly injected in the right and left main lobe of the liver. These rats had tumours at both sites of inoculation without extrahepatic tumour growth. The mean cross sectional area of these tumours (it x 0.25 x largest diameter x perpendicular diameter) on day 10 was 37 ± 13 mm
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
