TAC-101, A BENZOIC-ACID DERIVATIVE, INHIBITS LIVER METASTASIS OF HUMAN GASTROINTESTINAL CANCER AND PROLONGS THE LIFE-SPAN

We examined the anti-tumor effect of a novel benzoic acid derivative, TAC-101 (4-[3,5-bis(trimethyisilyl) benzamide] benzoic acid) on models with liver metastasis. Oral administration of TAC-101 significantly i nhibited spontaneous liver metastasis of AZ-521 (human gastric cancer) by orthotopic implantation to athymic nude mice. It also inhibited bo th the liver metastasis of AZ-521 induced by intrasplenic injection an d the secondary lung metastasis from the liver. In addition, TAC-101 i nhibited the proliferation of Co-3 (human colon adenocarcinoma) that f ormed a single nodule in the liver of athymic nude mice by intrahepati c implantation. The growth inhibitory effect of TAC-101 on AZ-521 expe rimental liver metastasis was observed when treatment was started on d ay 7, 14, or 21 which may correspond to the progressive stage of liver metastasis in clinical settings. Multiple administration of TAC-101 ( 8 mg/kg/day) significantly prolonged survival time of the animals with liver metastasis by intrasplenic injection of AZ-521 (T/C = 230%) and A549 (human lung adenocarcinoma; T/C = 186%), These effects of TAC-10 1 were stronger than those of 5-FU, CDDP or ATRA, Furthermore, TAC-101 inhibited the binding of AP-1 to DNA on electrophoretic mobility shif t assay using nuclear extract of AZ-521 cells, although ATRA did not i nhibit. These findings suggested that TAC-101 mag be a candidate for a new class of anti-cancer agents for liver metastasis. (C) 1998 Lippin cott-Raven Publishers.