Efficacy of gap junction enhancers and antineoplastic drugs in mammary carcinoma models

Doctor of PhilosophyDepartment of Diagnostic Medicine/PathobiologyThu Annelise NguyenPreclinical animal models of mammary carcinoma formation are vital for the advancement of cancer research, specifically in drug development. Two different types of animal models were utilized to determine the efficacy of combinational treatment of common antineoplastic drugs and the new class of primaquines that act as gap junction enhancers (PQs) at attenuating mammary tumor growth. The classic xenograft mouse model was used to show that PQs could increase the efficacy of cisplatin and paclitaxel. Combinational treatment induced an upregulation of connexin and caspase expression in the isolated tumor. Next the transgenic PyVT mouse model was characterized by multiple factors, including hormone receptor status, molecular markers for survival and proliferation, tissue histopathology, and secondary metastases during multiple stages of tumor development. This model showed limited therapeutic response to the antineoplastic drugs tested. PQ1 effectively attenuated tumor growth at all stages of tumorigenesis in the PyVT model, while PQ7 was determined to be an effective chemopreventive compound rather than chemotherapeutic. The PQs altered the expression profiles of connexins during tumorigenesis. Together the results indicate that PQs have an anticancer effect that is more efficient at attenuating tumor growth than the common antineoplastic compounds. Lastly the PyVT mouse model was used to determine the efficacy of antineoplastic compounds on male mammary carcinoma development. Interestingly, the antineoplastic compound that attenuated female mammary carcinoma growth did not produce a therapeutic response in the males and vice versa, suggesting a need for further studies into the male response to therapy