The value of regional intra-arterial therapy with novel sustained-release ethiodol based preparations for hepatic-neoplastic disease

We continue to search for effective therapies for hepatic-metastatic disease. Loco-regional therapy is attractive because it allows for tumour directed dose intensification without associated increase in systemic toxicity, which may lead to improved efficacy. In addition, the use of sustained-release or depot preparations may obviate the need for continuous infusion via expensive implantable pumps, and may also allow treatment of patients who are unfit for surgery, or who have more advanced disease. The iodinated poppyseed oil, Ethiodol, is selectively retained in liver tumours for weeks to months after hepatic intra-arterial infusion (HAI), and demonstrates ideal properties as a vehicle for development of depot or sustained-release HAI therapies of lipophillic or oil-soluble novel anticancer agents. This project demonstrated the value of Ethiodol for this purpose. A reproducible experimental animal hepatic-metastatic model using Fisher rats and syngenic MADB106 breast adenocarcinoma cells was established, and allowed evaluation of Ethiodol based HAI preparations. Several novel anticancer agents were soluble in Ethiodol and exhibited sustained-release characteristics. These preparations included (a) the topoisomerase-1 inhibitor 9-aminocamptothecin (9AC), (b) the cytokine human recombinant interleukin-2 (Hril2), and (c) several nitric oxide (NO) donors NOR1, NOR2, NOR3, SNAP and sodium nitroprusside. These compounds were effective antitumour agents both in vitro and in vivo, and inhibited tumour engraftment after subcutaneous inoculation with admixed tumour cells. They were well tolerated and eradicated hepatic-metastatic disease when administered as loco-regional HAI therapy, with decreased toxicity compared to equivalent systemic therapy. Investigation of mechanisms of antitimour activity revealed that macrophages appeared to be important for hRIL2 activity, and that NO and cyanide ion production appeared to both contribute to the effects of sodium nitroprusside. Results suggest that clinical studies of these compounds are feasible and warrant further investigation.