INVITRO MODE OF ACTION, PHARMACOKINETICS, AND ORGAN SPECIFICITY OF POLY (MALEIC ACID-STYRENE)-CONJUGATED NEOCARZINOSTATIN, SMANCS

Abstract

The organ specificity and pharmacokinetics of SMANCS, poly (maleic acid-styrene)-conjugated neocarzinostatin (NCS), were investigated in rats. The drug activity accumulated primarily in the region lymph nodes after s.c. injection. After i.v. injection, the drug was found in the kidney, lymph nodes and bladder in very high concentrations, and in lesser concentrations in the bone marrow, lung, small intestine, liver and spleen. The urinary excretion rate and total recovery of the drug after i.v. injection were higher than those after s.c. injection. SMANCS, having a MW of 2.5 .times. 104 daltons, was degraded in vivo to NCS (MW about 1.1 .times. 104). This was also confirmed in vitro by incubating the drug with cell homogenates. SMANCS caused strand scission of DNA similarly to NCS in lymphoblastoid cells. However, in a cell-free system using colicin E1 plasmid DNA, a high concentration of SMANCS was required to produce DNA degradation detectable by the alkaline sucrose gradient method. [SMANCS was developed as part of a search for antitumor agents that would localize in lymphoid tissue thereby exhibit antimetastatic activity.].