Tyrosine kinase inhibitors are an important group of target-specific, small molecule enzyme inhibitors that have been studied extensively and represent an expanding group of effective, chemotherapeutic agents. (8) These agents, unlike other cytotoxic agents, can be administered on a daily basis because of their selectivity and favorable safety profile. However, from previously conducted studies, all TKIs appear to be transported by efflux transporters and some of these have also been found to inhibit a few of their own metabolizing enzymes.(13) Pgp, BCRP and MRP1 have been known to facilitate the efflux of numerous conventional anticancer drugs too, including anthracyclines, vinca alkaloids and camptothecins.(25,26,27) Clinical investigations …show more content…
It has been demonstrated that TKI efflux occurs at low concentrations while inhibition of the transporter prevails at higher concentrations.(22,29,30) Since TKIs can be administered daily; there is also a higher chance for drug-drug interactions. In addition, the potential for drug-drug interaction increases when the substrates of efflux transporters are administered along with agents that inhibit the transporter activity. Plenty of such interactions have been reported previously and this influences therapy efficacy. For example, gefitinib reversed SN38 resistance in BCRP transfected cells by inhibiting the transporter function and increased topotecan intracellular concentrations.(7) Similarly, nilotinib inhibited the transporter function in a Pgp overexpressing tumor and enhanced paclitaxel concentrations synergistically. In …show more content…
Both these cell lines are known to express endogenous transporters (39) and results from these studies should be interpreted with caution. When uptake studies were done in LLC-PK1 wild type cells, dasatinib intracellular concentrations were found to be significantly increased in the presence of 50μM pazopanib and regorafenib. LLC-PK1 cells express endogenous BCRP and pazopanib and regorafenib were found to be significant BCRP inhibitors in our earlier uptake study with MDCK-II-BCRP cells. Therefore, it is likely that these endogenous BCRP transporters maybe responsible for the uptake change observed. Further, dasatinib intracellular concentrations significantly decreased in the presence of afatinib, bosutinib, gefitinib, imatinib, lapatinib, ponatinib, sunitinib and vandetanib. LLC-PK1 cells do not express OATP-C uptake transporters.(40) Dasatinib uptake studies in MDCK-II wild type cells revealed a slightly different trend. Among the 14 ingredients screened, 6 of them, namely, axitinib, erlotinib, imatinib, lapatinib, nilotinib and pazopanib exhibited a significant increase in dasatinib intracellular concentrations. MDCK-II cells have very little BCRP expression but have endogenous Pgp expression. Since axitinib, imatinib, lapatinib, nilotinib and pazopanib showed potent Pgp inhibition in the uptake study conducted in LLC-PK1-Pgp cells, the increased dasatinib uptake in MDCK-II wild
Pharmaceuticals have examined and found to ”work by changing the biological functions of the target cells in the body through chemical agents“ (Doweiko, 2015, p. 16). ”Many people in the past have thought that drugs that
G-protein-linked receptors are protein receptors, located in the plasma membrane of a cell, that work with G-proteins to activate a cell-signaling pathway. These receptors are structured similarly in most organisms, with seven α helices and specific loops for binding sites for signal molecules and G-proteins. When a signal molecule from the extracellular fluid attaches to the signal-binding site it activates the G-protein-linked receptor by changing its shape. When this happens, the G-protein, loosely attached to the cytoplasmic side of the cellular membrane, attaches to its binding side on the receptor protein. The inactive G-protein becomes activated when GDP is displaced by GTP, a molecule similar to ATP. When the signal molecule is released, the G-protein diffuses along the cell membrane and attaches to an inactive enzyme. This newly activated enzyme triggers the cellular response. When the protein detaches itself from the enzyme, it releases a phosphate group turning GTP back into GDP, making the G-protein inactive once again.
The molecular formula is C23H27FN4O2, with a molecular weight of 410.49 (Ereshefsky & Mascarena, 2003). Route of administration is oral. Once the drug passes the esophagus and stomach, it makes its way into the small intestines. There are beds of capillaries within the intestine walls.
...se them to become resistant to Gleevec. These mutations change the shape of bcr-abl to some extent that the treatment will not work on them, such that Gleevec can no longer bind to bcr-abl and activate it; which leads to gleevec resistance within patients with CML. Yet, using another Kinase inhibitor as an alternative to Gleevec which would block the mutated version of bcr-abl that causes resistance with Gleevec could be used to treat the new mutated version of bcr-abl. Such as: dasatinib, nilotinib, bosutinib, or ponatinib. Subsequently, even if the bcr-abl gene is not found in the patients blood, that still doesn't guarantee they are cured for now, so they are recommended to stay on the drug indefinitely. If all fails then patients are told to consider stem cell transplant as a last resort, especially for younger people who have a donor with a matching tissue type.
1. Discuss the structure of the plasma membrane and explain the process of active and passive transport through the membrane.
Altman, Lawrence K. ìShark Substance Found to Limit Tumor Growth.î New York Times 1 May 1996: A15.
Homeostasis is essential to the cell’s survival. The cell membrane is responsible for homeostasis. The membrane has a selective permeability which means what moves in and out of the cell is regulated. Amino acids, sugars, oxygen, sodium, and potassium are examples of substances that enter the cell. Waste products and carbon dioxide are removed from the cell.
Blockbuster drugs are usually a significant therapeutic breakthrough compared to previously available therapies. However greater therapeutic value alone is not enough for cr...
* We would have to leave one end open to fill it up with the different
Glucose is the primary source of energy for the cells and consequently is necessary for all cellular functions that require energy. Facilitated diffusion plays a significant role in the management of concentrations of glucose, both intracellular and extracellular, providing a balance of glucose in the cells that when poorly utilized upsets the body’s homeostasis.
The Importance of Diffusion to Living Organisms Diffusion is basically the movement of chemical species (ions or molecules) under the influence of concentration difference. The species will move from the high concentration area to the low concentration area till the concentration is consistent in the whole system. Diffusion mostly occurs in gases and liquids as these can move freely. The main features of an efficient diffusion system would be that it has a large surface area, thin membrane and a continuous supply of substances. A large surface area is needed so that high amount of substances can be exchanged at a time while the thin membrane means that the diffusion pathway would be short so that it is more efficient.
Chemotherapy drugs are more dangerous than other drugs because of their narrow therapeutic index. What is therapeutic index you ask? It is the ratio between a toxic dose and a therapeutic dose of a drug so any medication error with chemotherapy drugs could be a fatal one. Chemotherapy drugs can be very toxic even at the prescribed therapeutic level recommended by the physician. The findings in this article shows that the patient themselves are the first line of defense in spotting errors in medications they receive because they obs...
Cancer has been seen in humans as one the most potentially fatal disease for thousands of years and only in the recent couple of hundred years have we discovered that most information necessary to bring us to today’s understanding and knowledge (Kenny 2007, Weinberg 1996) was achieved by extensive research of cells, DNA, and epidemiology studies. As we know, currently cancer is acknowledged as having over a hundred different diseases, and is known to be the result of mutations of the genes and almost similar DNA which are responsible for the amount of cell division and production (Kenny 2007). Restraint of cell growth modulators can be a direct lead and result of certain tumours being developed and subsequently allow these tumours to acquire the ability to attack and occupy the bloodstream and essentially be able to travel via the bloodstream to other parts and organs in human bodies which is known as metastasis (Loeb et Al 2003). Once this has occurred , the cancer is then categorized as malicious and becomes a dangerous and serious threat to the carrier (Weinberg 1996). In this essay I will describe and explain the process of this and how our genes mutate and lead to metastasis of cancer cells.
Transport Across Plasma Membrane The plasma membrane covers all living cells, enabling the cells’ contents to be held together and controls movement of substances into and out of the cell. Plasma membranes are made of phospholipids, proteins and carbohydrates. The phospholipids are essentially made out of two fatty acid chains and a phosphate-glycerol group. They are arranged in a bilayer with the hydrophilic phosphate head facing outwards and the hydrophobic fatty acid chains facing inwards and to each other in the middle of the bilayer.
Exchange and Transport in Protozoa The exchange of gases between the environment and cells occurs via the process of diffusion. Diffusion depends on: · The amount of surface area available for diffusion. The larger the surface area the greater the rate of diffusion. · The concentration gradient. An organism which respires very quickly will have a much lower concentration of oxygen in the cells and a higher than normal concentration of Carbon Dioxide.