Synergistic Effect Between CRADs & TNP470 Concerning Apoptosis Induction Of Tumor Cells

To accomplish the satisfactory control of malignant disease, one of the feasible approaches is to find the effective combinations among various drugs or treatments. Genetic engineered adenovirus (generally called conditionally replication adnovirus, CRADs) as well as tumor angiogenesis inhibitor are two effective treatments. CRADs,as one of the genetic engineered adenovirus with the completion of E1B gene, replicate selectively in tumor cells, according to the difference between normal and malignant cells concerning the function of P53[1]. However, when it comes to tumor cells with wild type P53, the replication of the adenovirus is limited[2]. On the other hand, CRADs will also induce apoptosis of tumor cells through the pathway of E1A----P53----BAX. Therefore, as far as the treatment of wild type P53 tumor is being concerned, an important topic appears concerning the function of CRADs on apoptosis induction. TNP470, one of the tumor angiogenesis inhibitor, inhibits the tumor angiogenesis through competitive inhibition on epidermal cells' VEGF receptor[3]. Recently, TNP470 has been found to action directly on tumor cells in vitro, upgrade the expression of BAX, induce the apoptosis and inhibit the growth of tumors. Despite the concentration needed for apoptosis induction is further beyond the safe range of creatures, this finding has been followed and noticed widely and continually. This research aims to investigate the synergistic effect between CRADS and TNP470 concerning tumor treatment,discuss the possible mechanism of this synergism in the respect of apoptosis induction, and explore the feasible combination scheme between these two drugs. In this research, 84 615-mice, male, randomized into 7 groups (CRADs group, TNP470 group, 4 groups with different kinds of combined therapies, and N.S. control) and established with tumors by hypodermic injection with high-metastasis mouse liver cancer cells, underwent treatments respectively with corresponding drugs during 20 days; prohibition level on the tumors was detected in the terms of tumor weight and apoptosis percentage under scope, with bax detected by means of immunohistochemistry, while analysis was carried out among the different kinds of combination therapies to decide the best one. The results: Compared with the control, tumors in every therapeutic group were greatly inhibited in terms of tumor weight (P<0.01);in all therapeutic groups except TNP470 group, both apoptosis rate and bax positive rate increased compared with the control, with significant difference(P<0.01); compared with either single drug therapies or long-interval combined therapies, short-interval combined therapy (CRADs 108 Qd substituted with TNP470 60mg/kg Qd in 1-day interval) seemed more advantageous, suggested by upgraded BAX expression (0.85±0.06) and prohibited tumors weight (1.03±0.32g), (P<0.01).The factorial analysis suggested that synergism does exist between these two drugs in short interval combination scheme. Conclusions: Synergistic effect exists between CRADs and TNP470 concerning tumor treatment, the mechanism of which lies in enhanced apoptosis of tumor cells induced by escalated concentration of bax in the plasm, which may be explained as the amplification effect of TNP470 on the function of CRADs to upregulate BAX expression; short-interval combined therapy (CRADs 108 Qod and TNP470 60mg/kg Qod) can be adopted as an ideal scheme. The information pathway with cells involved with TNP470 may be one of the focuses in the future researches.