Question

How can a patient develop resistance to a chemotherapy drug? Describe the different mechanisms of drug resistance?

Answer 1

ANSWER:

There are several mechanisms by which a patient may develop a resistance to chemotherapy drugs, which are as follows-

• resistance in the survival cells-Some of the cells that survive the chemotherapy previously used may form resistant to the chemotherapy and these cells replicate and form a population of resistant cells that are now not-sensitive to the chemotherapy.
  
• drug efflux mechanism- Some of the family of the transporters such as ABC transporter which normally transport nutrients and molecules may also bind to and pump out the chemotherapeutic drug and pump it out of the cell. This mechanism enables the cell to show resistance to the chemotherapeutic drug.
  
• less drug intake- Specific chemotherapeutic drugs enter the cell by specific transporter protein molecules via passive diffusion, facilitated diffusion as well as active transport. But these transporter proteins might show resistance in the binding of the drug to the transporters as well as the number of those transporters may also get reduced. Thus these mechanisms will enable the cell to intake less amount of drugs inside.
  
• gene amplification-The gene amplification is one of the major ways by which a target cell(cancer cell) may show resistance to the chemotherapeutic drugs. The amplification of specific genes (such as oncogene) increases the amount of gene product more than a hundred-fold and that, in turn, results in the ineffectiveness of the drug.
  
• enhanced DNA break repair mechanism- Alterations in DNA break repair mechanisms are one of the significant ways by which a cell shows resistance. The nucleotide excision repair and Homologous recombination repair mechanisms play a key role in providing this resistance. The enhanced DNA repair mechanism enables these cells to overcome the effect of chemotherapeutic drugs and show resistance.
  
• altered drug metabolism- In order for the drug to show its effect on the target cells, the drug must be correctly metabolized, but in resistant cells, over-function of some enzymes and other alterations in the drug metabolism such as reduced activation of the pro-drugs, etc may render the drug not so effective. Thus these cells show resistance to the drug.
  
• tumor microenvironment -The role of tumor microenvironments in providing resistance to chemotherapeutic drugs is getting exposed day by day. There are various secreted factors, cytokine, etc that together have a role in the resistance shown.
  
• inactivation of the drug- depending on the cell types the resistant cell might develop some mechanisms(such as detoxification of the drugs) that inactivate the drugs after it is inside the cells.
  
• avoidance of apoptosis- The tumor cells very often becomes unresponsive to the apoptosis process by up-regulation of the anti-apoptotic genes. This one such mechanism that renders the drug ineffective in treatment.