Catálogo de publicaciones - libros

5-Fluorouracil (5-FU) has been the mainstay of colorectal cancer treatment for over 40 years. However, response rates for 5-FU in advanced colorectal cancer are modest. Although combining 5-FU with the newer chemotherapeutic agents oxaliplatin and irinotecan has improved response rates, new therapeutic strategies are necessary. Understanding the molecular mechanism by which tumors become resistant to 5-FU is needed if drug resistance is to be overcome. Tumor drug resistance is often due to insufficient chemotherapy-induced cell death. In this chapter, we describe the mechanisms of action of 5-FU, focusing on 5-FU-induced cell death. In the future, strategies aimed at increasing the effectiveness of 5-FU may target the cell death and cell survival pathways that are activated by this drug.

Endothelial progenitor cells (EPCs) and neural progenitor cells (NPCs) are promising for cancer therapy because they specifically target tumors. They have the capacity to home to, invade, migrate within, and incorporate into tumor structures. They are easily expanded and can be armed with therapeutic payloads protected within the progenitor cells. Once in the tumor, armed progenitors can be triggered to induce apoptosis in surrounding tumor cells. Pro-and antiapoptotic mechanisms are pivotal to effectively kill tumor cells while simultaneously protecting the cellular vehicles from premature demise. Increasing the ratio of tumor cell apoptosis to progenitor apoptosis will be crucial among other efforts to enhance the efficacy of endothelial and neural progenitor cells to a level sufficient for clinical application.

The observation that tumor development frequently is accompanied by apoptotic defects and the meanwhile accepted view that the vast majority of conventional anticancer agents primarily cause DNA damage to subsequently initiate the apoptotic machinery, have led to the conclusions that the capability to undergo apoptosis must contribute to the outcome of cancer therapy and that mutations compromising apoptosis might confer chemoresistance. However, experimental results from cellculture-based systems and conflicting data from the clinic have prompted reasonable doubts about a critical role of apoptosis in cancer therapy. This chapter highlights the technical difficulties in properly assessing the impact of treatment-induced apoptosis, discusses the value of more complex model systems, and underscores the relevance of apoptosis by providing insights from mouse models harboring tumors with genetically defined lesions and clinical observations based on novel proapoptotic compounds.

The interface between cell proliferation and cell death is thought to function as a pivotal crossroad essential to the preservation of normal homeostasis and to eliminate dangerous cells before they divide. Survivin is a prototype molecule at this crossroad, intercalated in protection against mitochondrial cell death and orchestrating various aspects of cell division. Dramatically exploited in cancer and an unfavorable gene signature for disease outcome, the survivin pathway provides tangible opportunities for targeted, rational cancer therapy.

Chromatin remodeling agents modulate gene expression in tumor cells. Acetylation and deacetylation are catalyzed by specific enzyme families, histone acetyltransferases (HATs) and deacetylases (HDACs), respectively. Aberrant acetylation of histone and nonhistone proteins has been linked to malignant diseases. HDAC inhibitors bear great potential as new drugs because of their ability to modulate transcription, induce differentiation and apoptosis, and inhibit angiogenesis. Furthermore, HDAC inhibitors also enhance the activity of other cancer therapeutics such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drugs, and radiotherapy. Some of the HDAC inhibitors are currently under clinical investigations. This chapter reviews the chemistry and the biology of HDACs and HDAC inhibitors, laying particular emphasis on those agents which have potentials for cancer therapy.