MP49-15 LOSS OF ZKSCAN3 IN BLADDER CANCER PROMOTES CELL PROLIFERATION, MIGRATION, AND INVASION

Abstract

INTRODUCTION AND OBJECTIVES: P16 (p16) is a key molecule of bladder tumor (BT) development, and we have previously reported that p16 antitumor peptide inhibited growth of subcutaneous BT graft through restoration of p16 function using Wr-T peptide transporter system in mice (Int J Oncol, 2013;42:543). Here, we evaluate the efficacy and toxicity of mouse p16 peptide administration on mouse lung metastasis model for BT. METHODS: Mouse lung metastases were developed by tail vein injection of p16-absent MBT-2 cell line. Six-week-old C3H/He female mice were divided into 3 groups as follows: control group (n1⁄412), single treatment group (n1⁄412) at 3rd experimental day and triple treatment group (n1⁄410) at 3rd, 5th and 7th experimental day. Treatment was also performed by tail vein injection using mixture of 80nmol mouse p16 and 50nmol Wr-T. At 14th experimental day, the lung metastases were histologically evaluated. As for the toxicity evaluation of p16 peptide transduction, low or high dose treatment was performed in five of 5-week-old C3H/He mice for each dose and evaluated by blood analyses and histological findings at early or late experimental phase. RESULTS: The lung metastases were observed in 100% (12/ 12), 41.7% (5/12), and 30% (3/10) in above three groups, respectively (Fig.). Size and number of lung metastatic tumor were significantly different between control and treatment groups (control vs single treatment group: p1⁄40.0014; control vs triple treatment group: p1⁄40.0007). In immunohistochemistry, phosphorylated Rb was decreased in lung tumor of treatment group as compared with that in control group. In both low and high dose groups, no remarkable change was found in body weight and blood analyses at early and late phase after m-p16 administration. No remarkable change was also observed histologically in bone marrow of treatment groups. CONCLUSIONS: Systemic p16 delivery could prevent lung tumor development on mouse BT metastatic model without severe adverse events assessed by blood analyses and histological evaluation.