What are drug resistance and multidrug resistance (MDR)?
Development of resistance: Drug resistance and MDR are major causes of treatment failure in cancer patients. When exposed to chemotherapeutic drugs, the cancer cell activates processes or synthesizes molecules that can inactivate or eliminate the drugs. Cancer cells have many alternative pathways at their disposal to overcome the toxic effects of chemotherapeutic drugs. Most of these mechanisms have origins in the normal cell. The oncologist recognizes the phenomenon of MDR and has developed treatment programs to delay its onset. Chemotherapy can consist of treatment with single drugs or multiple drugs. Chemotherapy is commonly combined with radiation or surgery. Research is ongoing to develop drugs that specifically target MDR when it develops.
Anticancer drugs have to overcome many challenges before they can accomplish their mission. Tumors are rapidly growing and have a poorly developed vascular system. The cancer cells have difficulty in receiving adequate oxygen and nutrients and therefore adapt to a hypoxic (low-oxygen) environment. This hypoxic environment can cause cancer cells to become resistant to drugs. Drugs have difficulty navigating the poor tumor vascular system to reach the cells. The drugs must be able to pass the cell membrane, navigate the cytoplasm, and reach the nucleus, where most drugs exert their effects. They must accumulate in high concentrations in their active form and must sustain these concentrations long enough to kill the cancer cell.
Drugs against MDR proteins: A major research focus is to develop drugs that counteract MDR proteins. The MDR proteins, known as drug efflux pumps, transport drugs out of cancer cells. These proteins belong to a family of proteins called the adenosine triphosphate (ATP) binding cassette proteins (ABCs). The ABC proteins are overexpressed (increase greatly) when exposed to chemotherapeutic drugs. These proteins reside in the cell membrane and consist of an embedded portion that forms a pore for transport of drugs and an internal portion that binds to the ATP molecule. When the ATP molecule is broken down, energy is released to drive the process.
P-glycoprotein is the main MDR protein that has been studied, and it remains of primary interest. Intensive research has developed first-, second-, and third-generation inhibitors to this protein, with each generation improving on the previous generation. Researchers have begun development of inhibitors that act by binding to the ABC protein and inhibiting its activity. The drugs have diverse chemical structures and origins.
Multidrug resistance-associated protein (MRP1) is also a major target of drug research. Several additional MRP proteins with structural similarities to MRP1 have been identified. Several other MDR proteins have been identified as well, including breast cancer resistant protein, mitoxantrone resistant protein, and others less well characterized.
Cellular changes associated with MDR: MDR is commonly associated with changes in the intracellular distribution of the chemotherapeutic drug. Most cancer therapies target deoxyribonucleic acid (DNA) or nuclear enzymes. When MDR develops, there is a redistribution of drug from the nucleus into cellular vesicles such as the Golgi apparatus, endosomes, and lysosomes. The drugs are then transported toward the plasma membrane and excreted from the cell by the process of exocytosis. This process of elimination is considered passive and is different from the MDR efflux pumps, which require energy input to proceed. The expression of MDR pumps is also associated with altered drug distribution within cancer cells.
Most chemotherapeutic drugs are mildly alkaline and have no charge. MDR cells have a more acidic pH inside subcellular vesicles than that of drug-sensitive cells. When drugs diffuse into the vesicles of MDR cells, they become protonated and take on a charge. The drugs are then trapped in the vesicles and cannot reach the nucleus to exert their effect. They can then be excreted from the cell by the process of exocytosis.
Glutathione and its associated enzyme, glutathionone-S-transferase (GST), are commonly found in the body and serve as a natural detoxification mechanism. GST can increase in the presence of a chemotherapeutic drug in the cancer cell. GST then catalyzes the binding of glutathione to the drug. The drug then becomes more water soluble, less toxic to the cell, and more readily excreted. Research is under way to develop drugs that inhibit GST and thus restore the cancer cell’s sensitivity to the drug.
Drugs that inhibit topoisomerase enzymes: The topoisomerase enzymes control the process of unwinding the DNA double helix during transcription or replication of the DNA molecule. This process is essential during cell division. Because cancer cells are rapidly dividing, topoisomerase inhibitor drugs are attractive treatments against a variety of cancers. To function, the drug must form a three-way complex with DNA and the enzyme. Conditions in the cell that interfere with this formation will lead to resistance. Mutations in the topoisomerase enzymes also cause resistance. Most topoisomerase inhibitors that have been the subject of clinical trials are derivatives of the plant extract camptothecin, although a semisynthetic derivative has also been developed.
Drugs that inhibit DNA synthesis: Rapidly dividing cancer cells have a great need for DNA synthesis, so anticancer drugs such as methotrexate and 5-fluorouracil have been used to block pathways to its synthesis. Methotrexate inhibits the enzyme dihydrofolate reductase, while 5-fluorouracil blocks the enzyme thymidylate synthase. Both of these enzymes are required for the synthesis of nucleotides, the building blocks of DNA. Methotrexate was introduced in the mid-twentieth century for the treatment of acute lymphoblastic anemia, but resistance occurs rapidly. Resistance to the drugs can be due to increased production of the target enzymes, defective transport of the drugs, or increased excretion by efflux pumps.
A number of chloroethyl- and methyl-nitrosourea therapeutic drugs attack the guanine unit of DNA in cancer cells to exert their toxic effect. The cancer cell acquires resistance to the drug by activating the enzyme O6-alkylguanine DNA alkyltransferase (AGT) to repair the damage. O6-benzylguanine inhibits the action of AGT and is used in the clinic in combination with nitrosourea drugs to reverse the resistance. Toxicity problems can occur when these drugs are used at levels needed to attain maximum effectiveness.
Protein kinase C is an enzyme that occupies a key role in the transfer of growth factor signals that result in DNA synthesis and cell division. This enzyme directly affects the expression of several proteins involved in drug resistance. These activities make protein kinase C an attractive target for therapeutic drugs.
Drugs that stimulate apoptosis: Most cancer drugs act by stimulating the process of apoptosis (programmed cell death). The susceptibility of a cancer cell to apoptosis depends on the balance between pro- and antiapoptotic proteins in the cell. When the TP53 protein (the primary proapoptotic protein) discovers genetic damage to the DNA molecule, it summons other proteins to halt cell division, and if necessary, to initiate apoptosis. Most cancers show mutations in the TP53 gene, so that instead of helping to destroy cancer cells, they can even promote cancer. Antiapoptotic proteins, particularly the Bcl-2 family, become more active during chemotherapy, leading to resistance to apoptosis.
Drugs that stimulate ceramide synthesis: Ceramide is the basic unit of sphingomyelin, a lipid structural element of cell membranes. Various stress stimuli, including radiation and chemotherapy, result in the formation of ceramide through the breakdown of sphingomyelin, or through synthesis from other molecules. Ceramide then acts as a second messenger relaying a signal to initiate apoptosis or other biological processes. MDR can result in a reduction in ceramide concentration through conversion to an inactive molecule. This reduces the effectiveness of chemotherapy, since many chemotherapeutic drugs exert their effect through apoptosis. Drugs are under development that increase ceramide levels in tumor cells by promoting ceramide synthesis or by blocking the conversion of ceramide to inactive compounds.
Side effects: Depending on the chemotherapeutic drug administered, a variety of side effects can occur. These can include nausea and vomiting, diarrhea and vomiting, anemia, malnutrition, cognitive effects such as memory loss, depression of the immune system, and toxicity to certain body organs.
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