Growth inhibition of colorectal liver metastases by combretastatin A4 prodrug (CA4P)

D. Kuruppu PhD, V. Muralidharan FRACS, C.M. Malcontenti-Wilson BSc, A. Misajon MSc, S. Skinner FRACS, PhD, C. Christophi FRACS, MD, P.E. O'Brien, MD, FRACS.

Dept of Surgery, Monash Medical School, Alfred Hospital, Prahran, Victoria 3181, Australia.

AIM: Liver metastases account for over 70% of deaths resulting from colorectal cancer. At present the only form of treatment with a curative outlook is surgical resection. CA4P is a vascular targeting agent that shrinks solid tumours by selectively targeting and destroying tumour specific blood vessels. The present study investigates the effect of CA4P on the growth of liver metastases in a murine model. METHODS: Liver metastases were induced by intrasplenic injection of a DMH induced colon cancer cell line in CBA mice. Tumour growth in this model occurs in 3 phases; a lag, an exponential, and a plateau phase over 3 weeks. Angiogenesis is evident at day 10, and exponential growth from day 16. A single dose of CA4P at 100mg/kg or 60 mg/kg was administered i.p. for 9 days beginning from day 10 post tumour induction, in the daily dosing study. CA4P at 60, 30, 10, 5, or 1mg/kg was given at day 10, 14, and 18 post tumour induction, in the intermittent dosing study. Tumour volume was determined at 3 weeks by stereology. Histology was studied by standard H&E staining. Data is presented as the mean+s.d., with T-test for statistical analysis, where p values < 0.05 were considered significant. RESULTS: Test Volume of Volume of Percentage of Daily Dosing Tumour Normal Liver Metastases Control 1626.4 +/- 1087.6 3106.8 +/- 1130.9 46.0 +/- 21.8 CA4P 100mg/kg 203.2 +/- 152.8* 1131.1 +/- 382.5 18.0 +/- 13.0* CA4P 60mg/kg 249.9 +/- 87.8* 1588.6 +/- 164.5 15.5 +/- 4.2* A marked inhibition of tumour growth is evident following daily administration of CA4P (*p<0.003). Comparable growth inhibition is observed following intermittent administration of CA4P, with 10 mg/kg being the lowest effective dose. Histological characteristics of CA4P treated tumours are consistent with an anti-vascular effect of the compound, where necrotic tumour cells surround a blocked vessel. This is in contrast to viable tumour cells that arrange concentrically around patent blood vessels. CONCLUSIONS: CA4P is a potent anti-vascular agent which is effective against liver metastases in this model.

KEY WORDS: combretastatin A4 phosphate, liver metastases, intrasplenic model, colorectal cancer, stereology.

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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 Dietary Influences.