Drug resistance and multidrug resistance (MDR)

• DEFINITION: Drug resistance is the loss of effectiveness of a drug used to kill or weaken cancer cells. It may be intrinsic—active in the cancer cell before treatment—or acquired—developed after treatment. Multidrug resistance (MDR) is the adaptation of cancer cells to withstand many structurally and functionally unrelated drugs designed to kill cancer cells.

Development of resistance: Drug resistance and MDR are significant 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 grows.

Anticancer drugs have to overcome many challenges before they can accomplish their mission. Tumors are rapidly growing and have a poorly developed vascular system. Cancer cells have difficulty receiving adequate oxygen and nutrients and adapting 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 get to the nucleus, where most drugs exert their effects. They must accumulate in high concentrations in their active form and sustain these concentrations long enough to kill the cancer cells.

Drugs against MDR proteins: A primary research focus is to develop drugs that counteract MDR proteins. The MDR proteins, or drug efflux pumps, transport drugs from cancer cells. These proteins belong to a family of proteins called the adenosine triphosphate (ATP) binding cassette proteins (ABCs). When exposed to chemotherapeutic drugs, the ABC proteins are overexpressed. These proteins reside in the cell membrane and consist of an embedded portion that forms a pore for the transport of drugs and an internal portion that binds to the ATP molecule. Energy is released to drive the process when the ATP molecule is broken down.

P-glycoprotein is the main MDR protein that has been studied and remains of primary interest. Intensive research has developed first, second, and third-generation inhibitors of this protein, with each generation improving on the previous generation. Researchers have begun developing 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 significant target of drug research. Several additional MRP proteins with structural similarities to MRP1 have been identified. Several other MDR proteins, including breast cancer-resistant protein, mitoxantrone-resistant protein, and others less well characterized, have also been identified.

Cellular changes associated with MDR: MDR is commonly related to changes in the intracellular distribution of the chemotherapeutic drug. Most cancer therapies target deoxyribonucleic acid (DNA) or nuclear enzymes. When MDR develops, drug redistribution from the nucleus into cellular vesicles such as the Golgi apparatus, endosomes, and lysosomes occurs. The drugs are then transported toward the plasma membrane and excreted from the cell by 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 drug-sensitive cells. When drugs diffuse into the vesicles of MDR cells, they become protonated and take on a charge. The drugs are 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, glutathione-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 becomes more water soluble, less toxic to the cell, and more readily excreted. Research is underway 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 rapidly divide, topoisomerase inhibitor drugs are attractive treatments against various cancers. The drug must form a three-way complex with DNA and the enzyme to function. 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 need DNA synthesis, so anticancer drugs such as methotrexate and 5-fluorouracil have been used to block pathways to its synthesis. Methotrexate inhibits the dihydrofolate reductase, while 5-fluorouracil blocks the 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 to treat 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.

Several 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-benzyl guanine 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 vital in transferring 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 facilitating 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 they can even promote cancer instead of helping to destroy cancer cells. 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, form ceramide through the breakdown of sphingomyelin or 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. Medicines that increase ceramide levels in tumor cells are under development by promoting ceramide synthesis or blocking the conversion of ceramide to inactive compounds.

Side effects: Various side effects can occur depending on the chemotherapeutic drug administered. 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 specific body organs.

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