PREPARATION, CHARACTERIZATION, AND ANTITUMOR EFFECTS OF A5B7-CMDEXTRAN-CISPLATIN CONJUGATES

The therapeutic use of cisplatin is limited by its toxicity to non-tar get tissues and its rapid clearance from the body by the kidneys. In a n attempt to improve the site-specific delivery of cisplatin and to st udy the pharmacokinetics of the conjugated drug we have linked it to t he anti-CEA (carcinoembryonic antigen) monoclonal antibody A5B7 via a carboxymethyldextran (CMdextran) carrier. At a conjugation ratio of 1: 3.3:50 (antibody: CMdextran:cisplatin) the conjugate was shown to reta in the ability to bind to CEA expressed on the surface of LS174T color ectal carcinoma cells and to cause dose-dependent cytotoxicity to the tumour cells in tissue culture. Control (non-CEA specific) antibody co njugates lacked this ability. When injected at a cisplatin dose of 5mg /kg into nude mice bearing the LS174T tumour, evidence of a targeting advantage by the A5B7-cisplatin conjugate was demonstrated by a small delay in the onset of tumour growth. This effect was not seen in a sim ilar experiment carried out at a higher cisplatin dose (10mg/kg).