The Effect of Cyclin - Dependent Kinase 4 and 6 Inhibition on Radiosensitivity in Breast Cancer Lines
Project no. 1102 · Status: Kapanmış · 2017
Summary
Cancer is a multi-step process of metabolic and behavioral pathways to the excessive and untimely proliferation of cells. Therefore, cancer is a disease with high incidence and mortality. There are carcinogens for breast cancers, cancer patients and pains. Today, although the survival rates of breast cancer patients have increased after the treatment, the mortality rate of cancers is changing. There are treatment methods in the presence of these cells. The morphology of the breast cancer variable is that a relapse disorder is unknown: breast cancer such as basal, HER2-positive breast cancer, lumen-A breast cancer and luminal-B breast cancer. The luminal-B breast cancer is the most promising new therapeutic target for therapeutic advances, with a very low end, therapeutic resistance and advances in molecular profiling. Lumen-B breast cancer together with other patients endocrine treatment, chemotherapy, radiotherapy is relatively insensitive to advanced. The Cell Cycle is Four Stages: G1 (Gap phase 1), S phase (DNA synthesis), G2 (Gap phase 2) and M phase (mitosis).Loss of normal cell cycle regulation has the characteristics of cancers. Irregular cell cycle patterns, oncogene and anti-oncogene are not significant in terms of voice induction and complication formation. The key regulator of the G1-S transition is the cyclin D-CDK4 / 6-INK4-Rb pathway. CDK4 / 6 coordinates cell cycle progression with cyclin D and reversible combination. The two-part complex of these elements phosphorylates cyclic tumor suppressors and transcription factors and contributes to the progress of the cell cycle. The key roles of CDK4 / 6 in cell cycle regulation make them effective targets for cancer therapeutic intervention, especially in breast cancer. In recent years, studies have been conducted to suppress cancer cell proliferation by targeting the CDK4 / 6 signal for effective cancer treatments. Several CDK inhibitors have been studied for potential tumor treatment and have been evaluated in terms of pharmacokinetics, efficacy and safety in many clinical trials. Theoretically important point is that CDKs play a critical role in the proliferation of cancer cells as well as normal cells, and potentially constitute a narrow therapeutic window in which toxicity limits the ability to achieve clinically effective exposure levels. Disregulation of the cyclin D-CDK4 / 6-INK4-Rb pathway is common in cancer and contributes to cell cycle progression and continued growth. Overexpression of D-type cyclins, mutation or amplification of CDK4 / 6 may occur through various mechanisms, including loss of cyclin D-CDK4 / 6 negative regulators such as P16INK4A, and ultimately lead to cancer cell development. Amplification of genes encoding cyclin D1 (CCND1), CDK4 or CDK6, or deletion of the locus encoding p16INK4A (cyclin-dependent kinase inhibitor 2A [CDKN2A]) are the main mechanisms by which the cyclin D-CDK4 / 6-INK4-Rb pathway can be activated. CDK4 / 6 inhibition decreases proliferation and causes cell cycle to stop. Because of the importance of CDK4 / 6 activity in regulating cell proliferation and the mechanisms by which this pathway has been activated in cancer, selective inhibition of CDK4 / 6 inhibitors has emerged as an attractive treatment strategy. Highly selective inhibitors for CDK4 / 6 have been researched and developed. It is possible that cancers with known deviations in the cyclin D-CDK4 / 6-INK4-Rb pathway are more sensitive to CDK4 / 6 inhibition than normal cells. Furthermore, selective inhibitors back up the activity of CDK2, which allows normal cells to function and proliferate. High-choice CDK4 / 6 inhibitors can therefore have a larger therapeutic window and less off-target toxicity. Palbociclib (PD-0332991; Pfizer), ribociclib (LEE011; Novartis) and abemaciclib (LY2835219; Lilly); three CDK4 / 6 inhibitors in approved or late-stage development. Radiotherapy is one of the cornerstones in the treatment of breast cancer patients. However, bre