Delivery of Doxil
The method for which Doxil enters a cell is similar to other liposomal drug delivery systems. It is originally injected through IV. Using specific targeting,; the drug is guided to cancerous cells. The liposome binds to the surface and releases Doxorubicin into the cell. Doxorubicin's Action Inside a Cell
The mechanism of action of Doxorubicin once it enters the cell is divided between two pathways, both of which are widely supported with evidence. 1) Doxorubicin disrupts topoisomerase-II-mediated DNA repair and double stranded replication. This destroys cells that are replicating. 2) Doxorubicin causes the production of Reactive Oxygen species. More Detailed Information of the Mechanism
(1) The Doxorubicin is intercalated into the DNA and disrupts topoisomerase-II-mediated DNA repair. This process occurs by formation of a Doxorubicin-proteasome complex to facilitate transport into the nucleus. Once inside the nucleus, the complex breaks down and the Doxorubicin binds to the DNA. The adriamycinone component of the Doxorubicin then intercalates the minor groove of the DNA double helix and the daunosamine aminosugar stabilizes the intercalation through binding of phosphate groups. This DNA/Doxorubicin complex then inhibits the action of topoisomerase-II—DNA complex. The result is double stranded breakage during replication, which stimulates cell death. (2) Doxorubicin generates free radicals, which cause damage to cellular membranes, DNA, and proteins. This occurs through the oxidation of Doxorubicin to semiquinone. It is believed that the enzymes (and their associated genes) that cause this oxidation are NADH dehydrogenase, nitric oxide synthase, and xanthine oxidase.The end result is the semiquionone. Semiquionone is an unstable metabolite; it will convert back to Doxorubicin in the process, releasing Reactive Oxygen Species (ROS). Important contributors to this mechanisms are proteins associated with deactivating free radicals. As such, it is believed that glutatione peroxidase, catalase, and superoxide dismutase play an important part. Regulation of these particular proteins can encourage cell death. The ROS produced through this process cause damage to the cell and breakdown of proteins and membranes. In addition, free radicals are formed. The end result is cell death. |
Thorn CF, Oshiro C, Marsh S, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenetics and Genomics. 2011;21(7):440-446. doi:10.1097/FPC.0b013e32833ffb56.
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