Metamorphosis of Neocarzinostatin to SMANCS: Chemistry, Biology, Pharmacology, and Clinical Effect of the First Prototype Anticancer Polymer Therapeutic

Summary

A polymer conjugated derivative of neocarzinostatin was prepared by cross-linking with two chains of poly(styrene-co-maleic acid half-butylate) (SMA) to neocarzinostatin (NCS), one at N-terminal alanine and the other at lysine 20. The conjugate was designated SMANCS. SMANCS exhibits a molecular weight of about 16000, and its oily formulation with Lipiodol (lipid contrast agent) became possible because of the hydrophobic property of SMA. When administered via the tumor-feeding artery, SMANCS in Lipiodol remained predominantly in tumor tissue: a concentration more than 2000 fold higher in the tumor than in the blood plasma. SMANCS showed increased stability in blood, and the immunogenecity was much lower than that of the parental NCS.

A predominant tumor-selective targeting mechanism was found not only for SMANCS administered intravenously as an aqueous formulation, but also was found later in many other macromolecular/polymer drugs as a common phenomenon if they were biocompatible. This mechanism is now called the enhanced permeability and retention (EPR) effect of macromolecules and lipids. These macromolecules circulate much longer in the blood and permeate solid tumors. Most solid tumors have a high vascular density and are defective in their anatomical architecture. Further, solid tumors produce multiple types of vascular permeability factors (e.g., bradykinin, nitric oxide, vascular permeability factors) that facilitate the vascular permeability of macromolecules to tumor interstitium. In addition, there is much less efficient clearance of these macromolecules from a tumor by the lymphatic system, thus they remain in the tumor for a long time. SMANCS also was shown to accumulate effectively in normal lymph nodes, thus it is considered beneficial as an anti-lymphatic-metastatic agent. In vitro studies showed that SMANCS is more effectively internalized into tumor cells and cleaves DNA.

The unprecedented clinical effect of SMANCS for human hepatoma is now well established; SMANCS became an approved drug in 1993 in Japan. The survival rate of hepatoma can be improved with SMANCS beyond 5 years; otherwise these patients usually die within 6 months. If hepatoma patients have no liver cirrhosis or metastasis to other organs, and the tumor is confined within one segment, the chances of 5-year survival could be as high as 90%. Future applications of SMANCS/Lipiodol with ascertained clinical benefit include treatment of renal cell carcinoma via the renal artery, metastatic hepatoma via the hepatic artery, and pleural and ascitic carcinomatoses using intracavitary application. Treatment of tumors of the lung, stomach, pancreas, and gallbladder, as well as lymphoma and melanoma with SMANCS/Lipiodol shows promise and awaits further evaluation. Major side effects are mild fever (50%), which usually lasts for a few days, and dull pain (about 30%), which lasts for a half-hour. Leucocytosis and immunological activation are seen frequently and they are beneficial effects. Hematological suppression and toxicity to the liver and kidneys are not usually observed.