abacavir and Breast-Neoplasms

The primary source of failure of cancer therapies is multidrug resistance (MDR), which can be caused by different mechanisms, including the overexpression of ABC transporters in cancer cells. Among the 48 human ABC proteins, the breast cancer resistance protein (BCRP/ABCG2) has been described as a pivotal player in cancer resistance. The use of functional inhibitors and expression modulators is a promising strategy to overcome the MDR caused by ABCG2. Despite the lack of clinical trials using ABCG2 inhibitors, many compounds have already been discovered. This review presents an overview about various ABCG2 inhibitors that have been identified, discussing some chemical aspects and the main experimental methods used to identify and characterize the mechanisms of new inhibitors. In addition, some biological requirements to pursue preclinical tests are described. Finally, we discuss the potential use of ABCG2 inhibitors in cancer stem cells (CSC) for improving the objective response rate and the mechanism of ABCG2 modulators at transcriptional and protein expression levels.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Proteins; Neoplastic Stem Cells

This article provides a general introduction into the field of pharmacogenetics and discusses its opportunities and limits. Pharmacogenetic research explores genetic variability between patients to explain observed differences in effectiveness of a drug therapy or adverse event profiles. Sometimes drug therapy is unfavourable: Patients may respond only partially to a drug therapy, do not respond at all, or suffer from serious adverse events. The reasons for the varying effectiveness of a drug therapy are due to factors like absorption; metabolism, elimination and target interaction. Recent research has led to a better understanding of the molecular genetic mechanisms behind those factors. Numerous new polymorphisms have been described, for example for the beta 2-adrenergic receptor or the cytochrome which can either improve or reduce the response to drug therapy. Two polymorphisms for the tumour necrosis factor alpha have shown to be associated with an increased risk of serious adverse events (hypersensibility: fever, rash, gastrointestinal symptoms) if treated with abacavir (HIV-treatment). Pharmacogenetic tests provide information about certain polymorphisms and raise the hope for an individualized pharmacotherapy. Yet, not only genetic but also environmental factors influence the effectiveness of a therapy. Even though results from research implies that pharmacogenetics has a great potential to maximize the effectiveness of pharmacotherapy and to reduce the incidence of drug-related adverse events, extensive clinical research both on effectiveness and costs is required to assess the true benefits of these exciting new technologies.

Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cohort Studies; Dideoxynucleosides; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Male; Mutation; Pharmacogenetics; Polymorphism, Genetic; Prognosis; Research; Reverse Transcriptase Inhibitors; Trastuzumab