ANTITUMOR EFFECTS AND TOXICITIES OF CARBOXYMETHYLPULLULAN-PEPTIDE-DOXORUBICIN CONJUGATES

In vivo antitumor effects of the conjugates of doxorubicin (DXR) with carboxymethylpullulan (CMPul) through tetrapeptide spacers were compar ed with those of DXR against tumor-bearing rats. CMPul-DXR conjugates bound through Gly-Gly-Phe-Gly and Gly-Phe-Gly-Gly spacers were found t o be more potent than DXR after a single intravenous injection in rats bearing Walker 256 carcinosarcoma. These conjugates were also more ef fective than DXR in rats bearing Yoshida sarcoma. However, CMPul-DXR c onjugate bound through Gly-Gly-Gly-Gly was less effective against Walk er 256-bearing rats than DXR. Body weight loss of CMPul-DXR conjugates in rats, on the other hand, was less than that of DXR at a DXR dose o f 10 mg/kg. Lethal doses of CMPul-DXR conjugates in CDF1 mice mere abo ut 3-times higher than that of DXR. These data suggest that the therap eutic index of CMPul-DXR conjugates bound through appropriate peptide spacers was increased more than that of DXR. However, CMPul-DXR conjug ates tested were all less effective than DXR against Walker 256 cells in vitro. Also, I-125-labeled CMPuI-DXR conjugate accumulated much les s in the cells than C-14-DXR.