Doxorubicin actions

The antineoplastic antibiotics, unlike their anti-infection antibiotic relatives, do not have anti-infective (against infection) abilily. Their action is similar to the alkylating dragp. Antineoplastic antibiotics appear to interfere with DNA and RNA synthesis and therefore delay or inhibit cell division, including the reproducing ability of malignant cells. Examples of antineoplastic antibiotics include bleomycin (Blenoxane), doxorubicin (Adriamycin), and plicamycin (Mithracin). 

In this situation, cell lines are shown to be resistant to colchicine, doxorubicin, vinblastine, and actinomycin D. This syndrome is accompanied by an increase in measurable membrane glycoprotein (the P-170 or permeability glycoprotein). It is believed that this protein transports hydrophobic chemicals out of cells and thereby prevents drug action. Current efforts to inhibit this efferent transport protein are currently underway but, sadly, have to date been largely unsuccessful (i5). 

The mechanism of action of daunorubicin and the indications for use are exactly the same as those of doxorubicin. Synonyms of this drug are daunoblastina, rabomycin, and cerubidine. 

Dexrazoxane (Zinecard) [Chelating Agent] Uses Prevent anthracycline-induced (eg, doxorubicin) cardiomyopathy Action Chelates heavy metals binds intracellular iron prevents anthracycline-induced free radicals Dose 10 1 ratio dexrazoxane doxorubicin 30 min prior to each dose, 5 1 ratio w/ CrCl <40 mL/min Caution [C, ] Contra Component sensitivity Disp Inj SE -1-BM (esp leukopenia), fever, Infxn, stomatitis, alopecia, NA /D Interactions t Length of muscle relaxation Wf succinylcholine EMS Given concurrent w/a chemo agent for treating CA to prevent cardiotox monitor for Infxn and reduced cardiac Fxn use caution w/ succinylcholine, reduced doses may be needed OD May cause extreme BM suppression symptomatic and supportive... 

Doxorubicin (Adriamycin, Rubex) [Antineoplastic/ Anthrocycline Antibiotic] Uses Acute leukemias Hodgkin Dz NHLs soft tissue, osteo Ewing sarcoma Wilms tumor neuroblastoma bladder, breast, ovarian, gastric, thyroid, lung CA Action Intercalates DNA X DNA topoisomerases I II Dose 60-75 mg/m q3wk X w/ hqjatic impair IV use only X... 

Peg Interferon Alfa 2b (PEG-Intron) [Antiviral/ Immunomodulator] WARNING Can cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disord s. Monitor pts closely Uses Rx Hep C Action Immune modulation Dose 1 mcg/kg/wk SQ 1.5 mcg/kg/wk combined w/ ribavirin Caution [C, X if used w/ ribavirin /-] w/ Hx psychiatric Contra Autoimmune H, decompensated Uvct Dz, hemoglobinopathy Disp Vials 50, 80, 120, 150 mcg/0.5 mL Redipen 50, 80,120,150 mcg/5 mL reconstitute w/ 0.7 mL w/ sterile water SE D ession, insomnia, suicidal behavior, GI upset, neutropenia, thrombocytopenia, alopecia, pruritus Interactions t Myelosuppression W/ antineoplastics t effects OF doxorubicin, theophylline t neurotox W7 vinblastine EMS See Peg Interf on Alfa-2a may cause flu-like Sxs... 

Trastuzumab (Herceptin) [Antineeplastic/Monoover express the HERlIneu. protein breast CA adjuvant, w/ doxorubicin, cyclophosphamide, and paclitaxel if pt HER2/neu(+) Action MoAb binds human EGF receptor 2 protein HER2) mediates cellular cytotox Dose Per protocol, typical 2 mg/kg/IV/wk Caution [B, ] CV dysfxn, alla-gy/inf Rxns Contra Live vaccines Disp Inj SE Anemia, cardiomyopathy, nephrotic synd, pneumonitis Interactions t Risk of cardiac dysfxn W/ anthracycline, cyclophosphamide, doxorubicin, epirubicin EMS Cardiomyopathy, ventricular dysfxn and pulm tox have been reported monitor for Sxs of reduced cardiac Fxn OD Sxs unknown... 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Idarubicin (Idamycin) differs from its parent compound, daunorubicin, by the absence of the methoxy group in the anthracycline ring structure. Its mechanisms of action and resistance are similar to those of doxorubicin and daunorubicin however, it is more lipophilic and more potent than these other anthracy-clines. Idarubicin undergoes extensive hepatic metabolism and biliary excretion. Adverse reactions of idarubicin are similar to those of its congeners. 

Ondansetron antagonizes the action of serotonin at receptors in the upper gastrointestinal tract and in the chemoreceptor trigger zone of the central nervous system. Given intravenously (IV), it prevents vomiting completely for 24 h in 40% of patients treated with high doses (>100 mg/m2) of cisplatin and in 70 to 80% of patients treated with 50 to 100 mg/m2 of cisplatin or a combination of cyclophosphamide and doxorubicin. 

Epirubicin is a doxorubicin analog whose mechanism of action is identical to that of all other anthracyclines. It was initially approved for use as a component of adjuvant therapy of early-stage,... 

Park, J. W., Kirpotin, D., Shalaby, R., Hong, K, Shao, Y., Marks, J., Papahadjopoulos, D., and Benz, C. C. (1998). Anti-HER2 immunoliposomes Significantly superior efficacy vs. doxorubicin, liposomal doxorubicin, and anti-her2 antibody treatment, via novel mechanism of action. Proc. Am. Soc. Clin. Oncol. 17, 216a. 

Therapeutic applications Applications for these two agents differ despite their structural similarity and their apparently similar mechanisms of action. Doxorubicin is one of the most important and widely used anticancer drugs. It is used for treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as acute lymphocytic leukemia and lymphomas. Daunorubicin is used in the treatment of acute lymphocytic and myelocytic leukemias. 

Figure 3.1 Combined effects of a combination of 7 anticancer drugs with different sites of action. Shown are the predicted (solid line concentration addition, broken line independent action), and the observed (circles) cytotoxic effects on DU 145 prostate cancer cells. Doxorubicin, daunorubicin, vincristin, cis-platin, etoposide, melphalan and 5-fluorouracil were combined at equitoxic concentrations. The mixture effect predictions were derived from the concentration-response curves of the individual anticancer drugs...

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