Microvascular Changes During Inhibition of Colorectal Liver Metastases by SMANCS/Lipiodol.

D. Kuruppu 1 PhD, H. Maeda 2 MD, C. Christophi 1 MD, FRACS, P. E. O'Brien 1 MD, FRACS

1Dept of Surgery, Monash Medical School, Alfred Hospital, Victoria 3181, 2Dept of Microbiology, Kumamoto University School of Medicine, Japan.

AIM: Liver metastases are the major cause of death resulting from colorectal cancer. The only form of treatment with a curative outlook is surgical resection. SMANCS/Lipiodol (S/L) is a macromolecular complex that targets the unique vascular architecture of tumour blood vessels. As tumour blood vessels are hyperpermeable, hypervascular, and lack a well developed lymphatic system, they exert an enhanced permeable and retention effect, which is targeted by SMANCS. Lipidol assists in selective tumour targeting. We investigate the effect of S/L on the growth and microcirculation of liver metastases in mice. METHODS: Liver metastases were induced by intrasplenic injection of DMH induced colon cancer cells. Tumour growth in this model occurs in 3 phases; lag, exponential, and plateau. Day 10 marks the onset of angiogenesis while day 16 denotes exponential growth. S/L (10 ng) was given as a single i.v. dose at day 10 or day 16. Tumour growth and microvascular architecture was observed at 3 weeks by stereology, histology and scanning electron microscopy (SEM) of corrosion casts. RESULTS: Tumour volume decreased from 1220+530 mm3 in the control to 480+/-360 mm3 and 590+/-340 mm3 in the day 10 and day 16 treated groups respectively (p<0.003). SEM of a control day 10 cast reveals avascular spaces (diameter 144+/-60 µm) not filled by the casting resin. These correspond to non-vascularised tumour cell aggregates on histology. By day 16 the tumours are larger depicting vascular branching. By day 21 a complex vascular architecture is evident. The vessel diameter increases from 150+/-70 µm at day 16, to 216+/-36 µm by day 21. Livers treated with S/L on day 10, observed at 3 weeks, are similar to day 10 controls. Day 16 treated livers, observed at 3 weeks, depict a branching vascular architecture, with increased tumour necrosis. S/L targets tumour microvessels when administered at both time points, markedly diminishing vessel size. CONCLUSION: S/L is a potent tumour inhibitory complex that targets the developing micorvessels of liver metastases.

KEY WORDS: SMANCS/Lipiodol, liver metastases, colorectal cancer, intrasplenic model, scanning electron microscopy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.

This presentation received an honorable mention in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.