Effect of DNA Repair Deficiencies on the Cytotoxicity of Drugs Used in Cancer Therapy - A Review
Current Medicinal Chemistry,
Jose Manuel Calderon-Montano, Estefania Burgos-Moron, Manuel Luis Orta and Miguel Lopez-LazaroAffiliation:
Department of Pharmacology, Faculty of Pharmacy, University of Seville, C/ Profesor Garcia Gonzalez, 41012, Sevilla, Spain.
AbstractTumor cells often have defects in DNA repair pathways that make them vulnerable to specific DNA-damaging anticancer agents. The identification of DNA repair defects in tumor cells and the evaluation of their influence on the cytotoxicity of anticancer drugs are active areas of scientific investigation that may help rationalize and improve cancer chemotherapy. This article reviews the available data on the influence of defects in proteins involved in the major DNA repair pathways (i.e., homologous recombination, non-homologous end joining, base excision repair, nucleotide excision repair, mismatch repair, Fanconi anemia repair, translesion synthesis and direct reversal repair) on the cytotoxicity of the FDAapproved anticancer drugs. It is shown that specific deficiencies in these DNA repair pathways alter the cytotoxicity of 60 anticancer drugs, including classical DNA-targeting drugs (e.g., alkylating agents, cytotoxic antibiotics, DNA topoisomerase inhibitors and antimetabolites) and other drugs whose primary pharmacological target is not the DNA (e.g., antimitotic agents, hormonal and targeted therapies). This information may help predict response to anticancer drugs in patients with tumors having specific DNA repair defects.
Anticancer, chemotherapy, DNA damage, DNA damage response.
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