Multidrug resistance

Multidrug resistance is the ability of pathologic cells to withstand chemicals that are designed to aid in the eradication of such cells. These pathologic cells include bacterial and neoplastic (tumor) cells.

Bacterial resistance to antibiotics

See main artilcle on Antibiotic resistance.

Microorganisms have been able to survive for thousands of years by their extreme adaptability when it comes to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer.

Bacteria have been able to adapt so that antibiotics are no longer effective. They have done this via several mechanisms.

• Inhibition of cell wall synthesis
• Enzymatic deactivation of antibiotics
• Decreased permeability (antibiotics can't get in)
• Altered binding-sites (kind of like changing the locks on the door)
• Increased efflux of altered cellular machinery (get rid of the broken parts)
• Interfere with DNA or RNA production/replication

Many different bacteria now exhibit multidrug resistance, including staphylococci, enterococci, gonococci , streptococci, salmonella, and others. Additionally, some resistant bacteria are able to transfer copies of DNA that codes for a mechanism of resistance to other bacteria, thereby conferring resistance to their neighbors, who then are also able to pass on the resistant gene.

To limit the development of antibiotic resistance:

• Only use antibiotics for bacterial infections
• Identify the causitive organism if possible
• Use the right antibiotic
• Don't stop antibiotics as soon as symtoms improve; finish the full course
• Most colds, coughs, bronchitis, sinus infections, and eye infections are viral; do not use antibiotics

Neoplastic resistance

Cancer cells also have the ability to become resistant to multiple different drugs. Cancer cells are those whose DNA has been modified such that the cells grow and reproduce at abnormally fast rates, no longer fulfill their intended roles, and often damage surrounding tissues. They in effect become parasitic organisms that feed off the body without regard to the health of the body. Two basic mechanisms are responsible for overgrowth: too much signal to grow or too little signal to stop growing. You might compare this to a car speeding out of control. If the accelerator is stuck down, the car keeps on going; if the brakes are shot, you can't stop the car. Two very important genes include ras and p53. Normal ras acts like the gas, so a mutation inactivates the gene and causes the cell to speed out of control. Normal p53 acts as a brake for cell division, so damaging the p53 gene reduces the cells ability to slow down when it comes to growth and reproduction.

Previously I mentioned that cancer cells grow and reproduce abnormally and ignore other tasks. What would happen if one of the tasks cancer cells neglected was pumping out toxic chemicals? The answer is toxic chemicals would build up inside cancer cells moreso than in normal cells, thereby preferentially causing harm to the cancer cells. Many of the mechanisms by which cancer cells become multidrug resistant are similar to those utilized by bacteria. These similarities include the following.

• Increased efflux of drug (as by P-glycoprotein, multidrug resistance associated protein, lung resistance related protein, and breast cancer resistance protein)
• Enzymatic deactivation (i.e. glutathione conjugation)
• Decreased permeability (drugs can't get in the cell)
• Altered binding-sites (kind of like changing the locks on the door)
• 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 are such a variety of different DNA mutations that cause or contribute to tumor formation as well as a myriad of mechanisms by which cells resist drugs. There are also certain notable differences between antibiotic drugs and antineoplastic (anticancer) drugs that complicate designing antineoplastic agents. Antibiotics are designed to target sites that are specific and unique to bacteria, thereby harming bacteria without harming host cells. Cancer cells, on the other hand, are altered human cells, and therefore they much more difficult to damage without also damaging healthy cells.

References

• Noble: Textbook of Primary Care Medicine, 3rd ed., Mosby, Inc. 2001.
• Guminski, A. (2002). Scientists and clinicians test their metal-back to the future with platinum compounds. The Lancet Oncology 3(5).
• Krishan, A. (2000). Monitoring of cellular resistance to cancer chemotherapy. Hematol Oncol Clin North Am. 16(2): 357-72.