Multiple drug resistance mechanism

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

Finally, some gram-negative organisms demonstrate a fourth mechanism of resistance. For example, strains of P. aeruginosa produce xenobiotic efflux pumps to eject antibiotics. Drug efflux mechanisms are associated with multiple drug resistance, including resistance to (3-lactam antibiotics. 

Komura, I., and K. Izaki. 1971. Mechanism of mercuric chloride resistance in microorganisms. I. Vaporization of a mercury compound from mercuric chloride by multiple drug resistance strains of Escherichia coli. J. Biochem. (Tokyo) 70 885-893. 

Kiba, T., Koyama, K., Ishiki, Y., Kimura, S., and Fukushima, T. (1960). On the mechanism of the development of multiple-drug-resistant clones of Shigella. Jpn J Microbiol 4, 219-227. 

Plasmid-mediated resistance to tetracyclines is widespread. Tetracycline-resistant organisms show decreased intracellular accumulation of the drugs. Resistance mechanisms include decreased activity of the uptake systems and the development of mechanisms (efflux pumps) for active extrusion of tetracyclines. Plasmids that include genes involved in the production of efflux pumps for tetracyclines commonly include resistance genes for multiple antibiotics. 

Ozben T. Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett 2006 580 2903 2909. 

UseAs sulfate for extrasystoles and atrial flutter, also for acute treatment. Not only Q. but also quinine are used in investigations of the mechanisms of multiple drug resistance of cancer cells against a series of chemotherapeutic agents. For biosynthesis, see Cinchona alkaloids. 

Liao, C.H., Pan, Si., Gnh, J.H., Chang, Yi., Pai, H.C., Lin, C.H., and Teng, C.M. (2005). Antitnmor mechanism of evodiartune, a constituent from Chinese herb evodiae fructus, in human multiple-drug resistant breast cancer nci/adr-res cells in vitro and in vivo. Carcinogenesis 26,968-975. 

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