? ? Novel agents are needed for achieving the goals of the growing interest and promise in developing chemoprevention approaches to cancer control (Sporn and Liby, 2005, Smith et al., 2005; Lippman and Lee, 2006; Francis et al., 2006). In pursuing nucleoside transport inhibitors as potential chemopreventive agents, we have discovered that dipyridamole is a potent chemopreventive agent against 12-O-phorbol-13-myristylacetate (TPA) tumor promotion in JB6 P+ cells. With an IC50 of 10 nM, dipyridamole is a much more potent than the known chemopreventive agent dehydroepiandrosterone (DHEA), which exhibited an IC50 of 1.0 ?M in the same JB6 P+ cell carcinogenesis assay. This application is thus planned to capitalize on this novel finding to conduct a structure-activity relationship (SAR) study, and use it to select compounds that will be evaluated as novel cancer chemoprevention agents in an in vivo animal model. New compounds for which synthetic methods have already been established in the applicant's laboratory will be synthesized and evaluated against 12-O-phorbol-13- myristylacetate (TPA)-induced tumor promotion in JB6 P+ cells. This application fits well with the timely program announcement (PAR-06-313), which has two of its objectives as the """"""""pilot testing and development of new methods of chemoprevention..."""""""" and the """"""""development and evaluation of molecular targets to prevent, reverse, or retard progression of precancerous lesions (and, hence, the cancer process) by natural, synthetic, chemopreventive agents."""""""" We are developing synthetic chemopreventive agents. We seek to achieve two specific aims in this application.
Specific Aim 1. To evaluate novel nucleoside transport inhibitors synthesized in the applicant's laboratory as antitumor promotion agents in vitro, and select potent and """"""""drug-like"""""""" compounds for in vivo animal testing.
Specific Aim 2. To investigate the chemopreventive ability of compounds selected from Specific Aim 1 in an in vivo mouse skin carcinogenesis model. A new AP-1-SEAP JB6 P+ cell reporter assay developed in the applicant's laboratory will be used in conjunction with an anchorage independent clonogenic assay to assess the in vitro chemopreventive activities of target compounds. Ancillary studies will also be undertaken to establish a rational basis for chemopreventive agent development. Thus, the determination of the levels and of activation of mitogen activated protein kinases (MAPKs) such as ERKs, p38 and JNK, which have been shown to be involved in tumor promotion signal transduction pathways in the JB6 P+ mouse epidermal carcinogenesis model, will be undertaken. The SENCAR mouse DMBA-initiation-TPA-promotion skin carcinogenesis model will be used for the in vivo studies in Specific Aim 2 to identify potential candidates for preclinical development as chemopreventive agents. Tumor incidence and multiplicity will be Histopathological and immunohistochemical analysis will be performed, as well as biomarker analysis of tumors that will be induced in the in vivo studies. The success of this project will expand our armamentarium of chemopreventive agents and uncover novel chemoprevention molecular targets. ? ? ?
| Wang, Chunmei; Schwab, Luciana P; Fan, Meiyun et al. (2013) Chemoprevention activity of dipyridamole in the MMTV-PyMT transgenic mouse model of breast cancer. Cancer Prev Res (Phila) 6:437-47 |
