SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy

This review discusses the development and therapeutic potential of prototyp e macromolecular drugs for use in cancer chemotherapy, in particular the de velopment and use of SMANCS, a conjugate of neocarzinostatin and poly(styre ne-comaleic acid). The various topics covered include a brief description o f the chemistry and polymer conjugation, the binding of the conjugate to al bumin and the biological behaviour in vitro and in vivo after arterial inje ction in animals, including plasma half-life, and the lipid solubility of S MANCS in medium chain triglycerides and Lipiodol, a lipid contrast medium s uitable for use in X-ray-computed tomography. The biological response-modif ying effects and the tumor-targeting mechanism of SMANCS and other macromol ecular drugs are also discussed. The latter mechanism is accounted for in t erms of a tumor 'enhanced permeability and retention' (or EPR) effect. A pr incipal advantage in the use of SMANCS or other macromolecular drugs is the potential for a reduction or elimination of toxicity. Macromolecular drugs such as a pyran copolymer-NCS conjugate show a marked reduction in bone ma rrow toxicity normally associated with the use of NCS. This is believed to be due to a hypothetical blood-bone marrow 'barrier' which, relative to NCS , restricts or limits access of the macromolecular drug to the bone marrow. In addition, the clinical possibilities for SMANCS are discussed, includin g the suggestion that angiotensin II-induced hypertension has clinical pote ntial in improving the selective delivery of macromolecular drugs (i.e. SMA NCS) to tumors. Aqueous SMANCS formulations have been tested in pilot studi es in patients with solid tumors of the ovary, esophagus, lung, stomach, ad renal gland and in the brain. Formulations based on SMANCS/Lipiodol have be en shown to be effective both as a diagnostic tool and for therapeutic use in solid tumors where the formulations are given arterially via a catheter. In a pilot study in primary unresectable hepatoma, an objective reduction in tumor size was observed for about 90% of cases when an adequate amount o f the macromolecular drug was administered. A patient receiving such treatm ent with no active liver cirrhosis and tumor nodules/lesion confined within one liver segment might expect to have a 90% chance of survival after trea tment for at least 5 years. (C) 2001 Elsevier Science BN. All rights reserv ed.