EFFECTIVENESS OF ISOLATED LIVER PERFUSION WITH MITOMYCIN-C IN THE TREATMENT OF LIVER-TUMORS OF RAT COLORECTAL-CANCER
EFFECTIVENESS OF ISOLATED LIVER PERFUSION WITH MITOMYCIN-C IN THE TREATMENT OF LIVER-TUMORS OF RAT COLORECTAL-CANCER
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DOI：
10.1038/bjc.1991.242
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发表时间：
1991-07-01
影响因子：
8.8
通讯作者：
VANDEVELDE, CJH
中科院分区：
文献类型：
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作者：
MARINELLI, A;DIJKSTRA, FR;VANDEVELDE, CJH
剂量限制性全身毒性阻止了充分利用大多数抗癌药物的陡峭剂量反应关系。 在我们的大鼠肝脏肿瘤模型（CC 531结直肠癌）中，隔离肝脏灌注允许给予比肝动脉输注更高剂量的丝裂霉素C，而全身毒性仍然很小。 为了确定丝裂霉素C诱导的细胞动力学变化的时间模式，我们分析了CC 531肝肿瘤的流式细胞术DNA直方图与高剂量丝裂霉素C（3.2毫克kg-1），通过肝动脉输注和处死大鼠在不同的时间间隔治疗后。 处理后12 ~ 36 h，S期和G2/M期细胞比例明显增加。 比较了在离体肝灌注和通过肝动脉输注中给予各自最大耐受剂量的丝裂霉素C对肿瘤细胞在细胞周期中的进展和对大体肿瘤生长的影响。 用丝裂霉素C隔离肝脏灌注导致治疗后24和48 h S中期和晚期细胞比例显著增加，并在早期S和G2/M期细胞中有一些积累。 相反，肝动脉灌注后，在处理后24 h观察到G2/M期细胞分数显著增加。 监测肿瘤生长后，7只大鼠中有5只表现出完全的肿瘤缓解，而在肝动脉灌注后，仅检测到最小的生长延迟。 本研究表明，大鼠CC 531肝肿瘤模型中的隔离肝灌注允许给予耐受良好的剂量的丝裂霉素C，该剂量足够高以诱导显著的DNA合成抑制，甚至完全的肿瘤缓解。
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.