[Recent advances in research on SMANCS].

During the past five years we observed many advances in the study of the polymer drug, "SMANCS". This first polymeric drug was approved by the Japanese Ministry of Health and Welfare in 1994 as a drug for primary liver cancer, in which the arterial injection of oily formulation in Lipiodol (a lipid contrast medium) is the standard procedure. The advantage of this tactic is the most extraordinary cancer targeting efficiency with the least systemic side effect and very prolonged slow release of SMANCS. The mechanism of tumor selective accumulation of SMANCS and polymeric drugs in general is discussed in view of the so called-EPR (enhanced permeability and retention) effect of solid tumor. The mode of action of SMANCS at the cellular level seems to accompany the generation of superoxide radical which damages DNA; strand break and modification of guaninine by 8-hydroxylguanine. Immunological potentiation involves either the cellular (M phi, T-cell, NK-cell) or molecular level (induction of cytokines, including interferon gamma). The in vivo effect of SMANCS is most pronounced in the tumor vessels where more concentrated SMANCS is accessible due to the EPR effect, and perhaps the generation of O2.-. Nitric oxide generated by both inducible form of NO synthase (iNOS) by the infiltrated macrophages and NOS of endothelial cells, and superoxide from SMANCS will readily react to form peroxynitrite (O2- + NO-->ONOO-), which is a very potent cytotoxic molecule and will damage (nitrate and oxidize) DNA and proteins. Thus, tissue damage and vascular injury or collapse will be the principle tumor toxic mechanism of SMANCS at tissue level. The dose of SMANCS (or grade I-IV tumor filling) and tumor regression parallel each other, and a profile of AFP-value and technical issues of SMANCS/Lipiodol administration intraarterially are also discussed.

[SMANCS/lipiodol].

SMANCS is the first commercially available polymer conjugated drug invented by the author, in which the protein antitumor agent neocarzinostatin is conjugated with two short chains of poly(styrene-comaleic acid) half-butylate. It exhibits the highest tumor/blood ratio (> 1,000) when injected arterially as an oily formulation in Lipiodol (SMANCS/Lipiodol). In addition, SMANCS/Lipiodol can give very high tumor contrasting image under X-ray (e.g., CT-scan), and thus the optimal dosing regimen can be determined and offers a diagnostic advantage. Phase I/II study of SMANCS was initiated in 1989 and it was approved by the Japanese Government in the fall of 1993 for the treatment of hepatoma. Exploitation of its application for other tumors such as renal cell cancer and pleural/ascitic carcinomatosis is anticipated. The response rate of Grad IV Lipiodol retention is 48.5% at 4 months; and those of 6 and 12 months are 50% and 90%, respectively. The major side effect is fever, which is only transitory, and no bone-marrow suppression, renal or hepatic toxicity were observed.

[Treatment of carcinomatous effusion with oily anticancer agents dissolved in lipiodol].

The oily anticancer agents dissolved in lipiodol used for arterial administration against various solid tumors in our department were found to be applicable to treat for pleural or peritoneal carcinomatosis experimentally and clinically. The pharmacokinetic study with rat model showed oily anticancer agents were retained in a high concentration in the peritoneal cavity compared to water-soluble anticancer agents. In our pilot clinical study all patients with pleural or peritoneal carcinomatosis showed improvement cytologically and physically.