Doxorubicin in Breast Cancer Doxorubicin is an antitumour antibiotic belonging to the family of anthracyclinewhich the classical ones (e.g.
rhodomycin) being cytotoxic and having narrowtherapeutic windows. But doxorubicin has been given interest because of itsanticancer effects in the treatment of many cancers including breast cancer,bladder cancer and lymphoma 1. Doxorubicin (sold under commontrade name Adriamycin) is commonly used in combination with other chemotherapydrugs with an injection into the vein being the mainly route of administration. The structure of the drug2 Disease target Doxorubicin is indicated for the control and treatment of a variety of humancancers including breast,ovarian, lung, bladder, thyroid, liver, and gastric cancers; Hodgkin’s andnon-Hodgkin’s lymphomas; Wilm’s tumor; soft-tissue sarcoma; neuroblastoma; andacute lymphoblastic leukemia. It is also used as part of the main adjuvanttherapy in women with confirmation of an axillary lymph node inclusionfollowing a resection of primary breast cancer 4. Molecular target Doxorubicin works mainly on the DNA. It workson the DNA in several ways with one being the intercalation (the squeezing ofthe drug between the base pairs of the DNA). This then leadsto alteration of the DNA structure and prevents the DNA from exercising itsnormal functions.
Doxorubicin also acts on the enzyme topoisomerase II which isresponsible for excising both strands of DNA helix at the same time which the purposeof controlling supercoils and tangles. This can lead to the termination of bothnormal cells (via topoisomerase II?) and in tumour cells (via topoisomerase II?) 5. The drug produces lipidmolecules known as ceramides which stimulate the cleaving of CREB3L1. Overexpression of CREB3L1 makes the tumour cells more sensitive to doxorubicinwhich results in altered gene that may contribute to the efficacy of the drug 6. Doxorubicin is also suspected to inhibit polymeraseactivity, affect regulation of gene expression, and also production of freeradical damage to DNA 7. Mechanism of action9 Doxorubicin is also known to to work by specificintercalation of the planar anthracycline nucleus with the DNA double helix. Inthis process, the drug is intercalated into the parts of the DNA free of nuclearproteins. This then leads to alteration of the DNA conformation which extendsto the histone octamer leading to the chromatin unfolding followed byaggregation 10.
Topoisomerase II is an enzyme which cuts both strands of DNA helix atthe same time which the purpose of controlling supercoils and tangles. This canlead to the termination of both normal cells (viatopoisomerase II?) and in tumourcells (via topoisomerase II?) thatare susceptible to doxorubicin 11. Doxorubicin acts by inhibitingtopoisomerase II activity by stabilizing the DNA-topoisomerase II complex.
Someof rings on doxorubicin do not intercalate into the DNA and this leads to thesustaining of the of the DNA-topoisomerase II complex. Since the DNA nickscannot be sealed, it leads to the build up of damage to the DNA which leads togrowth inhibition in the G1 and G2 phase hence leading to apoptotic cell death 12. Pharmacokinetics Thetoxic effects of doxorubicin is related to its peak concentration making therate of administration of the drug very vital. It is recommended to dilute thedrug with 0.9% sodium chloride over a 30-60minutes infusion or a fast runningIV drip. This is because higher peak concentrations may result from rapidintravenous bolus. Slower infusion rates also result in a greater area underthe curve and a longer distribution phase than a faster infusion rate andreduce toxic effects. Doxorubicin is metabolized in the liver and excreted inbile 13.
Doxorubicin can undergo 3metabolic routes: one-electron reduction, two-electron reduction anddeglycosidation. Doxorubicin is widely distributed with highest concentrationsin the liver, spleen, kidney, heart, small intestines, lung; its crosses theplacenta so can be found in breast milk. Doxorubicinol is the main active metabolite of doxorubicin of which 50-80% is bound to plasma protein.
Doxorubicin does not crossthe blood brain barrier. Elimination is mainly in bile (40-50%) within 5days and5-12% through urine as the drug and its metabolites over 5 days. The distributive half-life is 5 minutes with the terminal half life of thedrug is estimated to be 20-48 hours 14. Pathophysiology Doxorubicin is reduced by NADH dehydrogenase inthe respiratory complex I of the mitochondria to form a semiquinone radicalwhich in turn can also react with a molecule of oxygen to form a superoxide radical15. The formation of this free radical ends up producing toxic effectsin cardiomyocites.
A hydroxyl radical and hydrogen peroxide are then producedfollowing a series of redox reactions 16. The conversion of hydrogen peroxide to a hydroxylradical which is catalyzed by the formation of doxorubicin-iron complexgenerates a reactive oxygen species 17. Cardiomyocites are very sensitive to the oxidantstress that is caused by doxorubicin. The long term cardiotoxicity caused bydoxorubicin is characterized as a type I cardiotoxicity: cardiomyocyte deatheither through apoptosis or necrosis with the result not being reversible. Withdoxorubicin chemotherapy, a reduction in the left ventricular ejection fraction(LVEF) which may be asymptomatic was seen following a cumulative doses of >350 mg/m2 18.
PEGylatedliposomal is a form of doxorubicin delivery which reduces the cardiotoxicity byreducing the oxidative stress. Some beta-adrenergic receptor blockers such asCarvedilol has been suggested to possess some protection against leftventricular dysfunction induced by doxorubicin through its antioxidant characteristics19. Rationale for itsprescription Dueto the cardiotoxic effects doxorubicin has a drug of choice, it still provesproblematic in its use as an agent for breast cancer chemotherapy. Nonetheless,doxorubicin belongs to an important class of drugs in the treatment of cancer. Inthe administration of doxorubicin, cardioprotective therapies can be introducedat early stages especially in patients with high risk of developing leftventricular dysfunction induced by the drug. Beta blockers (especiallyCarvedilol) and Angiotensin II Receptor Blockers (ACE) inhibitors (especiallyenalapril) prevents decline in LVEF and late decline in LVEF respectively 20,21.Recent data shows that 31% of patients on doxorubicin chemotherapy with theirdecrease in LVEF being asymptomatic receive an ACE inhibitor or an angiotensinreceptor blocker. A beta blocker received by 35% with 42% being referred to seecardiologist 22.
Doxorubicin is hence used asan effective treatment option for breast cancer with effective preventativetherapies to prevent the cardiotoxic effects it may produce. The effectivecommunication between cardiologist and oncologist is invaluable in monitoringpatients on this drug and making sure they receive effective treatment and allnecessary steps taken to prevent and reduce the risk of its cardiotoxic sideeffect. References. 1 Arcamone, Federico. (1983). Structure-Activity Relationships inDoxorubicin Related Compounds.
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