Uncovering a new principle in chemotherapy resistance in breast cancer. Micrograph showing a lymph node invaded by ductal breast carcinoma, with extension of the tumour beyond the lymph node. Credit: Nephron/Wikipedia.
A laboratory study has revealed an entirely unexpected process for acquiring drug resistance that bypasses the need to re- establish DNA damage repair in breast cancers that have mutant BRCA1 or BRCA2 genes. The findings, reported by Andre Nussenzweig, Ph. D., and Shyam Sharan, Ph. D., at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues, appeared July 2. Nature. They help perform complex functions that facilitate the repair of damaged DNA. Individuals who inherit certain mutations in either the BRCA1 or BRCA2 gene have defective DNA repair and an increased risk of developing breast, ovarian, and other cancers.
Specifically, mutations in BRCA1 and BRCA2 account for 2. The reduced ability to repair breaks in DNA in cells with a BRCA1 or BRCA2 mutation makes the cells sensitive to DNA damaging drugs. However, breast cancers eventually acquire resistance to these drugs. One documented mechanism for developing chemoresistance in such tumors is through the restoration of accurate DNA repair pathways that mend DNA breaks caused by chemotherapy. Nussenzweig's laboratory has spent the past decade trying to understand the cellular mechanisms that regulate DNA repair in normal and pathogenic states.
Replication is a cellular process that produces two indistinguishable DNA copies from a single DNA molecule. This DNA- copying process is an essential step in cellular division and occurs at defined locations called replication forks.
The movement of a replication fork as it migrates along a DNA molecule can be disrupted by the presence of a diverse group of DNA structures and proteins, collectively and loosely referred to as replication fork barriers. This interruption of replication fork migration results in what is called a stalled fork. Upon replication fork stalling, the BRCA1 and BRCA2 proteins are called upon to protect the newly synthesized strands of DNA. If these proteins are absent, the replication fork is destabilized and the newly synthesized DNA is degraded, which increases genomic instability and increases sensitivity to DNA- damaging drugs. The investigators were able to identify other proteins, such as PTIP, CHD4 and PARP1, that actively promote replication fork destabilization through the recruitment of enzymes that degrade newly synthesized DNA.
The absence of these proteins protected the DNA at replication forks and remarkably reversed the drug sensitivity of both BRCA1- and BRCA2- mutant cells, making them chemoresistant. These studies also highlighted the complex ways by which tumor cells can evade chemotherapeutic interventions and acquire drug resistance, since disrupting the activity of multiple proteins led to the same end point of replication fork protection. These results are of particular relevance in the clinical setting, where expression of these proteins appears to be an indicator of how patients with BRCA1- and BRCA2- mutant cancers will respond to chemotherapeutic treatment with DNA- damaging agents. All together, these results underscore the importance of replication fork barriers to genomic instability and drug sensitivity in the context of BRCA1/2 mutations. The results also suggest that the cellular levels of these proteins could be used as a prognostic factor in acquired resistance in BRCA1/2- mutant cancers. Replication fork stability confers chemoresistance in BRCA- deficient cells, Nature (2. DOI: 1. 0. 1. 03.
Chemotherapy with cytotoxic anticancer agents remains the mainstay of therapy targeted at specific cellular mechanisms in malignant disease. Principles of chemotherapy ppt 1. PRINCIPLES OF CHEMOTHERAPY Dr. Introduction: Introduction Cancer chemotherapy is a branch of cancer treatment that involve the use of chemical agents to destroy cancer cells.
Adjuvant/neoadjuvant chemotherapy studies generally employ regimens that have appeared most active against the same tumor in advanced stages.
Chemotherapy will not be administered if documentation of written consent is incomplete at the start of the first dose or at change in chemotherapy regimen. Principles of Clinical Cancer Chemotherapy and Drug Resistance. Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology.
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a category of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents. Cancer chemotherapy zHowever with this theory, cells near the surface would divide about 30 times more than cells in the center and therefore a. Electrochemotherapy is a type of chemotherapy that allows delivery of non-permeant drugs to the cell interior. It is based on the local application of short and.