Clinical resistance to anticancer drugs is the primary reason for treatment failure in pediatric oncology.
Drug resistance can be present from the start of therapy (intrinsic) or can develop under selective pressure of drug exposure (acquired).
Mechanisms of Drug Resistance:
- Decreased drug uptake by the cell
- Increased drug excretion out of cell
- Detoxification of drug by the cell
- Increased DNA repair
- Alterations in structure of drug receptor sites
- Decreased apoptosis
The development of drug resistance has a genetic basis. Tumor cells are genetically unstable and so drug resistant clones arise spontaneously as a result of mutation, deletion, gene amplification, translocation or chromosomal rearrangement.
MULTIDRUG RESISTANCE GENE (MDR):
- Intrinsic MDR present in tumor prior to treatment.
- Acquired results from genetic mutation following chemotherapy.
- Results from a protein (P-glycoprotein).
- Rapidly eliminates drug from cell (efflux pump) e.g. anthracyclines, vinca alkaloids.
- Research exploring causes/prevention.
Chemosensitizers under development which can reverse multi-drug resistance caused by P-glycoprotein.