Sandbox Reserved 390: Difference between revisions
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The purpose of this page is to explain a semisynthetic derivative of [http://en.wikipedia.org/wiki/Podophyllotoxin podophyllotoxin] [[Image:PODO.png|thumb|right|50 px|Chemical structure of podophyllotoxin]] (etoposide) that demonstrates antitumor activity by inhibiting DNA topoisomerase II, thereby inhibiting DNA re-ligation which lead to apoptosis of the cancer cell and also, to describe the mechanisms of resistance of etoposide. | The purpose of this page is to explain a semisynthetic derivative of [http://en.wikipedia.org/wiki/Podophyllotoxin podophyllotoxin] [[Image:PODO.png|thumb|right|50 px|Chemical structure of podophyllotoxin]] (etoposide) that demonstrates antitumor activity by inhibiting DNA topoisomerase II, thereby inhibiting DNA re-ligation which lead to apoptosis of the cancer cell and also, to describe the mechanisms of resistance of etoposide. | ||
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'''1.''' Decreased accumulation via increased P-glycoprotein (a multidrug resistance): This drug resistance mechanism is characterized by decreased intracellular accumulation of drug facilitated by overexpression of the human multidrug resistance (mdrl) gene, causing overproduction of P-glycoprotein. This cell membrane protein acts as an export pump for a wide variety of unrelated foreign natural products. By maintaining lower intracellular levels of drug, lower drug concentration would be available to the target, which is topoisomerase II. | '''1.''' Decreased accumulation via increased P-glycoprotein (a multidrug resistance): This drug resistance mechanism is characterized by decreased intracellular accumulation of drug facilitated by overexpression of the human multidrug resistance (mdrl) gene, causing overproduction of P-glycoprotein. This cell membrane protein acts as an export pump for a wide variety of unrelated foreign natural products. By maintaining lower intracellular levels of drug, lower drug concentration would be available to the target, which is topoisomerase II. | ||
[[Image:PGP.gif|thumb|right|500 px|P-glycoprotein as a transmembrane drug efflux pump]] | [[Image:PGP.gif|thumb|right|500 px|P-glycoprotein as a transmembrane drug efflux pump<ref>doi:10.1038/nrc823</ref> | ||
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'''2.''' Changes in target proteins: This mechanism relates directly to the target enzyme; Either low enzyme levels or altered sensitivity of the enzyme for the drug confers resistance to that drug. This mechanism also confers a form of multidrug resistance; in that resistance to one topoisomerase II inhibitor through decreased or altered topoisomerase activity generally translates into resistance to most other topoisomerase II inhibitors. | '''2.''' Changes in target proteins: This mechanism relates directly to the target enzyme; Either low enzyme levels or altered sensitivity of the enzyme for the drug confers resistance to that drug. This mechanism also confers a form of multidrug resistance; in that resistance to one topoisomerase II inhibitor through decreased or altered topoisomerase activity generally translates into resistance to most other topoisomerase II inhibitors. | ||
