Enhancement of macrophage and natural killer cell antitumor activity by DIVEMA-adriamycin conjugate

Divinyl ether and maleic anhydride (DIVEMA) is a synthetic polyanion known to stimulate antitumor activity in macrophages (Mφ) and natural killer cells (NK). This compound is used as a carrier of anticancer drugs because of its efficient covalent binding and release of anti-cancer drugs. Recently, the conjugate of DIVEMA with adriamycin (ADM) was reported to have higher tumor control activity in mice-bearing intraperitoneal dissemination of fibrosarcoma (FSaI) cells than either DIVEMA or ADM alone. We here report on the effects of intraperitoneal (ip) injection of this conjugate on the cytotoxicity of peritoneal Mφ and splenic NK against FSaI cells. The conjugate clearly enhanced Mφ cyotoxicity, the maximum cytotoxicity being obsereved 7 days after ip. This cytotxicity enhancement was similar to the activation by DIVEMA, but it was stronger than that by ADM alone. On the other hand no activation of splenic NK by administration of either the conjugate or ADM was observed, despite remarkable NK activation by DIVEMA. These findings indicate that a part of the immunostimulatory activity of DIVEMA remains in the conjugate when DIVEMA is used as a carrier for ADM. Consequently the data also suggest that the antitumor effects of the conjugate resulted from combined effects of the host-mediated activity and the direct cytotoxicity of ADM itself.