Potentiation of the activity of cisplatin in a human colon tumour xenograft model by auristatin PYE, a structural modification of dolastatin 10

Abstract

Dolastatin 10, a marine natural product peptide, is now known to act as a vascular disrupting agent (VDA). These VDA properties were not known when other aspects of its promising pre-clinical profile led to initial unsuccessful clinical trials. Auristatin PYE, a synthetic analogue of dolastatin 10, has demonstrated improved activity in preliminary in vivo studies. However, as with other VDAs, tumour eradication was incomplete due to the maintenance of functional vasculature supporting the viable tumour at the periphery of the tumour xenograft, meaning that once the VDA effect subsides, the tumour regrows. One possible strategy for removing this peripheral tumour involves combining VDA therapy with another anticancer drug with a different mechanism of action. Here, we evaluated the effect of combining auristatin PYE with cisplatin in an HCT-116 human colon adenocarcinoma xenograft model. The effects on the growth of subcutaneously implanted HCT-116 xenografts in mice following intraperitoneal administration of a single dose of 4 mgkg−1 cisplatin and intravenous administration of 1 mgkg−1 auristatin PYE were evaluated compared to the effect of each agent administered alone. The effects on the functional tumour vasculature were also assessed. Statistically significant potentiation (p<0.01) was noted with a 465% growth delay for the combination group compared to the control, and 142 and 310% growth delays for the cisplatin and auristatin PYE groups, respectively. Shut down of tumour vasculature in the combination group was similar to that observed with auristatin PYE on its own. Auristatin PYE demonstrated synergistic antitumour effects when combined with cisplatin, suggesting that a combination chemotherapy regimen would be the most effective strategy when applying this new anticancer drug.