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Antineoplastic resistance is the drug resistance of neoplastic (cancerous) cells to one or more chemotherapeutic drugs. Mechanisms are comparable but not identical to drug resistant microorganisms such as bacteria, fungi and viruses. Cancer cells have the ability to become resistant to multiple drugs by many mechanisms:


 * Increased efflux of drug (as by P-glycoprotein (ABCB1), multidrug resistance-associated protein (ABCC1), and breast cancer resistance protein (also known as mitoxantrone resistance associated protein, MXR, or ABCG2)
 * Enzymatic modulation
 * Decreased permeability (drugs cannot enter the cell)
 * Altered binding-sites
 * Alternate metabolic pathways (the cancer compensates for the effect of the drug).

Because efflux is a significant contributor for multidrug resistance in cancer cells, current research is aimed at blocking specific efflux mechanisms. Treatment of cancer is complicated by the fact that there is such a variety of different DNA mutations that cause or contribute to tumor formation, as well as myriad mechanisms by which cells resist drugs.

Notable differences between antibiotic drugs and antineoplastic (anticancer) drugs that complicate their design are that cancer cells are altered human cells and thus more difficult to damage without damaging healthy cells.

Types of resistance
The defining characteristic of resistance is the ability of a cell to survive the tumour growth inhibiting properties of chemotherapeutic drugs. Although chemotherapy is an effective and efficient way to treat cancers, many cancerous cells have the ability to develop a resistance to these drugs (chemoresistance). Such resistances appear in a number of different types of cancers and tumours including blood, breast, ovarian, lung and gastrointestinal tract cancers. The majority of these tumours consist of a combination of drug-sensitive and drug-resistant cells, however with subsequent treatments these cell populations become increasingly resistant as the drug-sensitive cell population is destroyed and the drug-resistant phenotype becomes dominant in the population (see positive selection).

Intrinsic resistance
Some cancer cells are fundamentally immune to antineoplastic treatments due to some heritable trait. These cells are fairly uncommon and typically occur only once in a population of 10⁶-10⁷ cancerous cells.

Acquired resistance
Cancerous cells have the ability to establish a resistance to many forms of cancer treatments over time after exposure to treatment. This protection develops as a result of direct exposure to the drug or treatment.

Mechanisms of resistance
Many of the mechanisms involved in antineoplastic resistance in cancer cells most likely originated as a foundational defense system in normal cells against naturally-occurring toxins in the environment.

Altered membrane transport
Altered membrane transport is among the most effective forms of antineoplastic resistance as it acts directly on the intracellular concentration of the chemotherapy drugs. Central to this process are ATP-dependent multidrug transporters, membrane proteins belonging to the family of ATP-binding cassette (ABC) proteins. These genetically encoded proteins regulate the uptake or exclusion of antineoplastic treatments by pumping cytotoxic molecules across the plasma membrane of cancerous cells. The most notable of these tumour-cell molecular pumps are the ABC transporter P-glycoprotein, encoded by the multidrug resistance gene 1 (MDR1) gene, the associated multidrug resistance protein (MRP) and the breast cancer resistance protein (BCRP). P-glycoproteins have 12 transmembrane domains and two ATP-binding-sites. Binding of two ATP, non-simultaneously, is required to pump one drug molecule out of the cell. Resistance results in low intracellular concentrations of the drug, therefore reducing and limiting the drugs effect. Intrinsic resistance has been linked to the overexpression of multidrug transporters that has been observed in many types of tumours including lung, colon and liver.

Enzymatic modulation
Enzymes that metabolize drugs may confer drug resistance by decreasing the concentration of chemotherapeutic drugs in cells. Cytochrome P450 (CYP) is a protein (in extrahepatic tissue) that contributes to drug resistance by activation and deactivation of cytotoxic drugs via metabolism. CYPs exist in different phenotypes that are specific to their ability to metabolize metabolites (drugs, precarcinogens, etc,). There are uncommon phenotypes of CYP that have been linked to the incidence of various types diseases including certain types of cancer. A possible mechanism of resistance would be metabolism resulting in deactivation of the anti-cancer drug, resulting in inactivation of the drug. Some polymorphisms of CYP can be useful in cancer treatment through a few pathways. CYP is expressed at higher levels in cancer cells as opposed to normal/healthy tissue. Drugs that are activated by CYP would therefore specifically target cancer cells and limit harm to normal tissue.

Hypoxia
The rapid and uncontrolled division of tumour cells results in a hypoxic condition. Survival of tumour cells relies heavily upon the upregulation of growth and transcription factors that are triggered this low oxygen environment within cells. Hypoxia also increases expression of genes that code for multidrug transporters such as P-glycoprotein and MRP. Several cancer drugs require oxygen to produce the reactive oxygen species (ROS) that target and damage cancer cell DNA and thus become ineffective in low oxygen environments.

Decreased drug uptake
Drugs that are water-soluble can ‘piggyback’ on transporters that are normally used to carry nutrients into the cell. They can also use endocytotic means to enter the cell. In some cells lacking evidence of increased efflux, the drugs still fail to accumulate. However, the mechanisms which initiate this resistance are poorly understood.

Treating resistant cancers
The treatment of neoplastic cells is dependent on the type of cancer and is specific to the case. The most widely used forms of cancer treatment involve surgery, radiotherapy and chemotherapy. However, simply increasing dosage of chemotherapeutic drugs is not a rational strategy to overcome antineoplastic resistance. Systems with rapidly reproducing healthy cells, such as the gastrointestinal tract and hematopoietic system, are highly affected by chemotherapeutic toxicity. For this reason, dosages are often decreased during chemotherapy regimes to reduce treatment complications. However, the tolerable dose of many chemotherapeutic drugs is quite close to the minimal threshold for effective treatment, which also reduces the likelihood of tumor eradication. Targeted chemotherapy and induced resistance in healthy tissue is currently being researched as a solution. Other research has identified Combination drug therapy as another possible solution to overcoming resistance to cytotoxic drugs.

Induced resistance
Animal models have shown promising results, including integration of MDR1, dihydrofolate reductase (Dhfr) and methylguanine methyltransferase (MGMT) genes into healthy tissues. Only MDR1 has been tested in human trials, but has failed to demonstrate efficacy of treatment to this point.

Gene therapy
Retroviral vectors with synthesized multidrug resistance genes with high expression can be used for targeting of hematopoietic cells as a means of resistance to cytotoxic cancer drugs. In this process, hematopoietic pluripotent stem cells are extracted from bone marrow and transfected by engineered viruses. The cells are then transfected back into the patient conferring hematopoietic system resilience, allowing higher and more effective dosages of cancer drugs.

Combination drug therapy
P-glycoprotein antagonists are effective in disabling the efflux of drugs from the cancer cells and used in combination with chemotherapeutic drugs result in the maintenance of a high concentration of cytotoxic molecules within the cell thereby dismantling the tumour’s resistance to treatment. Furthermore, proteins associated with multidrug resistance can be targeted by engineered monoclonal antibodies which act to repress P-glycoprotein activity in cancer cells.

DNA damage
Many chemotherapy treatments aim to damage DNA, which preferentially causes cell death in rapidly reproducing cancerous cells. Because cancerous cells often have at least one DNA repair mechanism damaged, they are preferentially selected against during treatment regimens. When cells detect DNA damage, cell cycle arrest is initiated, preventing cell division and generally leading to apoptosis. When exposed to chemotherapy drugs, however, there is a strong positive selection for resistant cell lines in highly heterologous tumors. Resistance is developed through many functions, including variably abundant transcription of oncogenic or tumor suppressing genes, modified binding-sites, and increased expression of DNA repair enzymes in undamaged pathways.