Benzo-Fused Seven- and Six-Membered Derivatives Linked to Pyrimidines or Purines Induce Apoptosis of Human Metastatic Breast Cancer MCF-7 Cells In Vitro

Abstract

In recent years, strategy in cancer therapy has been the use of high doses of toxic nonspecific agents and to investigate a range of new agents that specifically target tumourrelated molecules, in a variety of biological pathways. A basic knowledge of these pathways in the cancer cell is becoming fundamental for clinical practice since it can provide prognostic as well as predictive information for established therapies, and lead to the discovery of potential new targets. Two main therapeutic strategies may be followed to optimize cancer treatment: a better selection of patients who will benefit the most from a given hormonal o cytotoxic therapy, through the use of predictive markers determined by genomics and/or proteomics techniques and the development of new agents with innovative and tumour-specific mechanism of action. We have reviewed the consideration of Choline Kinase as a novel target for the development of new anticancer drugs (Campos et al., 2003). Breast cancer is a common and often fatal disease. Excluding cancers of the skin, that of the breast is the most common cancer among women, accounting for nearly one out of every three cancers diagnosed in American women. Each year over 186,000 new cases and 46,000 deaths are reported in the United States alone (Harris et al., 1996). Five main molecular pathways are of particular interest in terms of new drug development in breast cancer: the estrogen receptor pathway, the tyrosine signal transduction pathway, the angiogenesis pathway, the cell cycle regulation pathway and the apoptosis (programmed cell death) pathway. We will focus in this review on new cytotoxic, apoptotic and cell-cycle-regulator agents, designed by our Group. As part of their action on neoplastic cells, many anticancer drugs activate apoptosis that may be a primary mechanism of antineoplastic agents (Hickman, 1992). Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells using these drugs (Rasbridge et al., 1994). Improved clinical response may be obtained by identifying therapies that are particularly effective in