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Resistance to Anticancer Drugs-1

© David Olle

The resistance to chemotherapeutic drugs in cancer patients is particularly frustrating. Quite commonly, patients initially show a good response to treatment only to succumb to the disease. The cancer cells can develop resistance not only to the drug being administered, but also to many other drugs that are dissimilar in structure and act at different intracellular targets. This phenomenon is known as multiple drug resistance. The reasons why this happens is the focus of this article.

Remember that cancer cells derive from normal cells and tend to maintain the usual physiological functions to protect themselves from poisons that could harm them. Resistance to anticancer drugs can be either intrinsic (present in the cancer cell before treatment) or acquired after treatment. In addition, the resistance can be multiple, or (less commonly) limited to one drug or drug family. 1 Cancer cells are noted for their enhanced proliferative rate, which in turn is dependent on the proper functioning of their DNA. Anticancer drugs, therefore, usually target DNA or nuclear enzymes involved in DNA functioning. They must enter the nucleus of the cell to exert their effects. Unfortunately, the toxic side effects of chemotherapeutic drugs limits the maximum dose that can be administered, which is often inadequate to kill cancer cells.

There are many hurdles placed in the way of anticancer drugs that can prevent them from accomplishing their assigned task of killing cancer cells. The first problem is inadequate drug delivery to the cancer cells. Tumors are supplied by blood vessels that can have many abnormalities resulting in reduced delivery of drug. In addition, some cancer cells in the center of tumors may not be supplied by blood vessels, become dormant and insensitive to the drug. There is evidence that if they are later revived by new blood vessel formation they may become more aggressive and likely to spread.

The second problem is in maintaining adequate drug concentration in the cells. Cancer cells often show alterations in their intracellular compartments (Golgi apparatus, endosomes, and lysosomes), resulting in changes in locations and increases in size. These changes can result in an increase in sequestering or capture of anticancer drugs. There is also evidence for an increased turnover of drugs in the compartments. As a result, the drugs do not reach the nucleus, but are excreted by the cell. 4

Two genes code for the formation of proteins that are involved in the transport of drugs out of the cell. Multiple drug resistance gene codes for P-glycoprotein (Pgp) and multidrug resistance-associated protein gene codes for multidrug resistance-associated protein (MRP). Although these proteins perform roles in normal tissues, they are overexpressed in cancer cells. There is evidence that the simultaneous activity of the two proteins is the decisive factor in the resistance of tumor cells to anticancer drugs. 4

The copyright of the article Resistance to Anticancer Drugs-1 in Cancer Treatment is owned by David Olle. Permission to republish Resistance to Anticancer Drugs-1 in print or online must be granted by the author in writing.