Preclinical pharmacology of novel synthetic iminoquinones as anticancer agents.

摘要

Prostate cancer is the most common male malignancy and the second leading cause of cancer related death in the United States. Despite recent advances in the detection, diagnosis, and treatment of prostate cancer, there is a need for more effective therapies. Unfortunately, most conventional therapeutic modalities, such as androgen ablation therapy, frequently result in androgen-independent cancers. These cancers are typically more aggressive, metastatic, and resistant to chemotherapeutic agents than androgen-dependent prostate cancer. Therefore, agents that are effective against both androgen-sensitive and androgen-independent, as well as genetically diverse cancers are critically needed.;The objective of the dissertation research was to address the first arm of preclinical drug development: the assessment of efficacy. Two novel synthetic compounds, BA-TPQ and FBA-TPQ, were selected following an initial in vitro efficacy screen of approximately forty iminoquinone analogs. The major results obtained from these studies revealed that (1) BA-TPQ and FBA-TPQ exhibit dose-dependent cytotoxicity in the low micromolar range, inhibit proliferation, induce cell cycle arrest, and induce apoptosis in prostate cancer cell lines; (2) FBA-TPQ decreases the expression of the androgen receptor and PSA; (3) FBA-TPQ inhibits the growth of prostate cancer xenograft tumors; (4) the iminoquinones are effective against prostate cancer cell lines regardless of their p53 or hormone receptor status; (5) FBA-TPQ and BA-TPQ are stable under physiological and experimental conditions and bind considerably to plasma proteins; (6) the synthetic iminoquinones are widely distributed in murine tissues following intraperitoneal and intravenous administration.;Additional studies from our laboratory have shown that BA-TPQ and FBA-TPQ exhibit anti-cancer effects in models of breast cancer, pancreatic cancer, and lung cancer, further demonstrating that these compounds present a viable new option for cancer therapy. Future studies investigating these compounds in other models of cancer and in combination with other anti-cancer therapeutic agents would be of interest. Collectively, the results of these preclinical evaluations contribute to the knowledge of iminoquinone-related anti-cancer activity, mechanisms of action, and pharmacokinetic properties.