Abstract: "Multidrug Resistance in Cancer."

September 28, 1990

Kartner, Norbert, and Victor Ling. "Multidrug Resistance in Cancer." Scientific American, March 1989, 44-51.

Why are some cancers curable by chemotherapy itself, while others are unaffected by drugs and are apparently incurable?

In average tumor of detectable size, there can be hundreds of millions of cells. In the cell population, about one in each million cells will be a drug-resistant mutant. A drug used to destroy the tumor will kill off all the non-mutant cells. However, the mutant will still be able to live and reproduce, thus continuing the growth of the tumor. Also, the mutant's children cells will also be resistant to the drug. To combat this, a large amount of drugs would be used to fight the tumor. Unfortunately some cells have been discovered to be resistant to almost all drugs.

Scientists believed that the reason some cells were resistant to many drugs was either a permeability barrier, or a mechanism that pumped drugs out of the cell. When cyanide was used to inhibit the cell's energy production, the cell acted like a regular cell which was not resistant to drugs; therefore, the pump appeared to be the best explanation.

After examining drug-resistant cells, a protein which was found in only a small number of other cells, was found in great abundance. Named P-glycoprotein, it was found to resemble a membrane transport protein. It was located on the cells membrane. P-glycoprotein was also found to have a lengthy hydrophilic region, which was known to be located on the inner side of the cell membrane. At this region, an ATP binding site was found. Also, it was found to be very similar to a protein known as hemolysin B - a protein found in bacteria that transports the protein, alpha-hemolysin into and out of the cells. In drug-resistant cells, P-glycoprotein probably acts in a similar fashion, 'pumping' out drugs.

P-Glycoprotein is thought to be used in standard cells to remove toxins from cells. This feature evolved to help prevent cells from being affected by toxins secreted by enemy cells. The glycoprotein may also have been be used in other transport processes. It was found to be located in the kidneys, adrenal glands, liver, and parts of the gastrointestinal tract of a normal adult. All of these tissues are involved in the transporting a variety of transportation and secretion processes.

Methods are now being studied to kill the P-glycoprotein- containing, drug-resistant cells. A variety of compounds have been found which inhibit the function of P-glycoprotein. After first using these compounds, an anti-tumor drug would be effective in killing the formerly drug-resistant tumor cell. Another method of fighting these cells would be to create a special anti-P-glycoprotein drug.

The author uses an illustration of P-glycoprotein to display the structure and function of the protein. This drawing enhances the article by providing a view of the structure of this protein. Without the drawing, it would be much more difficult to understand the general structure of P-glycoprotein. The drawing also provides some insight into the function of P-glycoprotein.

This article answers questions concerning why cells are drug-resistant. It also explains the function of P-glycoprotein. However, it brings up further questions. Some of the questions include: How might we enhance the present tumor-removal processes? What other functions are there of P-glycoprotein? and Is P-glycoprotein the only cause of cell's drug-resistance?