AVN-316

CDDP, commonly used in cancer chemotherapy, behaves as not only effector but also modulator of 5-FU when combined with 5-FU and the derivatives. Therefore, the antitumor activity of combination treatment of BOF-A2, a new 5-fluorouracil derivative, with CDDP was evaluated with two human lung cancers (H-74 and LC-376) xenografted in nude mice. BOF-A2 was orally administered at 30 mg/kg (MTD) or 15 mg/kg (1/2 MTD) 3 times a week totally twelve times, and CDDP was administrated interperitoneally at 5 mg/kg (MTD) or 2.5 mg/kg (1/2 MTD) once a week totally 4 times. The antitumor effect of combination of two drugs at the 1/2 MTD was effective to H-74 and markedly effective to LC-376, and the effect was more remarkable than each drug administered individually at the 1/2 MTD, and the combination effect was additive. The effect by the combination was not synergistic but showed a similar activity compared with single drug given individually at the MTD. Moreover, the side effect of combination of the 1/2 MTD was less than group given MTD of CDDP in terms of body weight loss. These data suggests a clinical usefulness of combination BOF-A2 with CDDP against lung cancer.

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.