Drug resistance, gene amplification

Gene amplification 1 Many oncogenes are present in multiple copies erbB amplified in certain breast cancers Dihydrofolate reductase genes are amplified in some tumors, leading to drug resistance... 

Augmented drug extrusion increased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipodophyllotoxins, and paclitaxel) is re-ponsible for multi-drug resistance (mdr-1 gene amplification). 

The most recognized and studied mechanisms of drug resistance are attributed to multidrug resistance (MDR), gene amplification, DNA repair. 

Slovak, M., Ho, J., Cole, S., Deeley, R Greenberger, F de Vries, E Broxterman, H., Scheffer, G., and Scheper, R. (1995) The FRP gene encoding a major vault protein associated with drug resistance maps proximal to MRP on chromosome 16 evidence that chromosome breakage plays a key role in MRP or FRP gene amplification. Cancer Res. 55,4214-4219. 

Surprisingly, a method of antifolate resistance commonly cited in tumor cells is gene amplification resulting in increased target protein and decreased anti-folate efficacy, which has yet to be identified in any clinically relevant isolate. A further difference in antifolate resistance between mammalian cells and the parasitic cell is altered polyglutamation of die antifolate drugs. In mammalian cells, folates are taken up by a folate transport system and once inside the cell are poly-glutamated to trap the folates intracellularly. A reported mechanism of resistance in the cancer cell is the loss of... 

F. (1989) Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244 1184-1186. 

Figure 5. Overexpression of PTRl, a known methotrexate resistance protein, in a drug resistant strain of L. major (strain MTX 60.2). A. Comparison of 2D gel images revealed a highly overexpressed spot in the resistant mutant versus the wildtype. MALDI-TOF analysis identified the spot as PTRl. B. DNA amplification (visible in the ethidium bromide-stained panel to the left) is a common mechanism of protein overexpression in Leishmania. Southern hybridisation using a PTRl probe (right panel) confirmed a substantial amplification of the PTRl gene, providing a mechanism for the overexpression seen by 2D gels.

Ouellette M, Hettema E, Wust D et al. Direct and inverted DNA tepeats associated with P-glycoprotein gene amplification in drug resistant Leishmania. EMBO J 1991 10 1009-1016. 

Ouellette M, Borst P. Drug resistance and P-glycoptotein gene amplification in the protozoan parasite Leishmania. Res Microbiol 1991 142 737-746. 

In human leukaemia, the malignant white blood cells readily develop resistance to methotrexate (4.7) when treated with this drug. At the same time, an excess of DHFR, the enzyme that methotrexate is employed to block, is found in the patient s leucocytes (Bertino et al., 1965). The 200-fold increase in this reductase found in murine sarcoma and lymphoma cells which became resistant through methotrexate treatment, has been traced to induction, by the drug, of extra copies of the gene (Alt et al., 1978). For more on such gene amplification, see Fox (1984), Borst (1984). 

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