Anthracycline seminar
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This presentation describes about discovery mechanism of action, metabolism, mechanism of resistance and pharmacokinetics of anthracyclines
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Anthracycline seminar
- 1. Anthracyclines- antitumor antibiotics Savitha Varatharajan
- 2. Outline of the presentation • Discovery • Chemistry • Mechanism of action • Mechanism of resistance • Toxicity • Pharmacokinetics
- 3. Castle del Monte, Italy
- 4. Discovery of anthracyclines Dr. Fedrico Arcamone Dr. Aurelio Di Marco Farmitalia Research Laboratories of Milan, Italy Streptomyces peucetius Daunorubicin was isolated from Streptomyces coeruleorubidus in Rhone –Poulenc laboratories in France and was named Cerubidine
- 6. Anthracyclines in treatment of cancer Anthracycline Cancer Doxorubicin Cervical cancer, breast cancer, pancreatic cancer, Lung cancer, thyroid cancer, Multiple myeloma Daunorubicin Acute leukemias (ALL, AML), Kaposi Sarcoma Idarubicin AML, ALL, CML, MDS, Non Hodgkins Lymphoma Epirubicin Breast cancer, lung cancer, bladder cancer, ovarian cancer, head and neck cancer, hepatocellular carcinoma Oxford American Handbook of oncology by Gary. H. Lyman
- 7. Other anthracyclines Acute myeloid leukemia Prostate cancer ( not responding to hormone therapy) Breast cancer Non-Hodgkin’s Lymphoma Acute myeloid leukemia Breast cancer
- 8. Anthracyclines- Mechanism of action
- 9. Nature 201,706-707 (15 Feb 1964)
- 10. Anthracycline mechanism of action Anthracycline semiquinone ROS Apoptosis Alteration in mtDNA Disruption of Ca2+ homeostasis Impairment of energy metabolism Cytosol Anthracycline aglycone (Oxidizers) Anthracycline alcohol metabolite Impairment of iron homeostasis Nucleus DNA intercalation Topoisomerase IIa poisoning Modified from Mordente,A et.al;Advances in Mitochondrial Medicine, Advances in Experimental 385 Medicine and Biology
- 11. Topoisomerase IIα (Top2a) Homodimer with three different domains per unit. Localised in the nucleus and thought to be expressed during proliferation stage Involved in reversible Double Strand Breakage Target of anthracyclines Mechanism of Action of Top2a
- 12. Anthracycline interaction with iron Elena Gammella Front. Pharmacol., 26 February 2014
- 13. Mechanism of resistance Elevated expression of efflux transporters Increased metabolism of the drug into inactive metabolite. Microenvironment Hypoxia microRNA
- 14. ABC transporters in anthracycline resistance James I Fletcher; Nat Rev Cancer. 2010 Feb;10(2):147-56.
- 17. Elevated ABCC3 and ABCB6 expression in Daunorubicin resistant AML samples Manuscript in preparation
- 18. Metabolism of anthracyclines as a mechanism of resistance
- 19. Enzymes involved in anthracycline metabolism Aldoketoreductases (AKR) AKR1A1 AKR1B1 AKR1C1 NAD(P)H dehydrogenase, quinone 1 (NQO1) Short Chain Dehydrogenase (SDR) Carbonyl Reductase 1 (CBR1) Carbonyl Reductase 3 (CBR3)
- 20. Expression of CBR confers resistance to Daunorubicin ●K562 control. 72 hours exposure 2 hours + 72 hour growth Daunorubicin (nM) K562 cells transfected with hCBR cDNA showed increase in resistance to daunorubicin2 2.Basilio Gonzalez.et.al.,Cancer Research 55, 4646-4650, 1995 3. Mariann Plebuch.et.al., Cancer Letters 255 (2007) 49–56 EPP85-181P human pancreas adenocarcinoma transfected with three different enzymes involved in carbonyl compound metabolism3 CBR1 expressing cells metabolized daunorubicin 7 fold higher compared to AKR1A1 and AKR1B13 Conversion of Dnr to Dnrol was seen in ML1 and KG1 which expressed CBR. 1 1.Geetha Vasanthakumar and Nahed K. Ahmed Cancer Chemother Pharmacol (1985) 15:35-39
- 23. Hypoxia and anthracycline resistance J.Hepatol.2011 Feb;54(2):328-39.
- 24. Hypoxia and anthracycline resistance
- 25. Tumor microenvironment mediated anthracycline resistance
- 26. Matsunaga; Nature Medicine 9, 1158 - 1165 (2003)
- 27. Role of miRNA in anthracycline resistance 1.FEBS Letters 585 (2011) 402-408 2. Mol Med Rep. 2014 May;9(5):1909-16 3. [Mol Cancer Ther 2008;7(7):2152–9]
- 29. Toxicity/Adverse Events Bone marrow suppression Nausea and Vomiting Alopecia Infertility Secondary malignancies Elevated hepatic enzymes Encephalopathy Mucositis Cardiotoxicity
- 30. Cardiotoxicity Nat Rev Clin Oncol. 2013 Dec;10(12):697-710
- 31. Effect of cumulative dose of anthracycline on cardiotoxicity US Pharm. 2014;39(2):HS2-HS10.
- 32. Mechanism of anthracycline mediated cardiotoxicity Nat Rev Clin Oncol. 2013 Dec;10(12):697-710
- 33. Cardiotoxicity in DS-AML Cardiovasc Toxicol. 2015 Jan 24. [Epub ahead of print]
- 34. Strategies to overcome toxicity Slow infusion Anti-oxidants Iron chelators (Dexrazoxane) Liposomal anthracycline Pegylated anthracycline Extracellularly Tumor activated prodrugs Morpholinyl anthracycline Alkyl anthracyclines Disaccharide anthracyclines Therapeutic drug monitoring
- 35. N. Engl. J. Med.351(2),145–153 (2004).
- 36. Other cardioprotectants Probucol- Anti-oxidant and lipid lowering agent N-Acetyl Cystein- Mucolytic agent with anticarcinogenic and antigenotoxic properties Carvedilol- β adrenergic antagonist, potent antioxidant Angiotensin- converting enzyme (ACE) inhibitors Sildenafil- Phospho diesterase -5 inhibitor
- 37. CPX-351 Liposomal formulation of a synergistic 5:1 molar ratio of Cytarabine and Daunorubicin http://www.celatorpharma.com/#!cpx-351/c22gy
- 38. Therapeutic drug monitoring of anthracyclines
- 39. Pharmacokinetics of anthracyclines Triexponential model with high initial peak.
- 40. Plasma pharmacokinetic parameters of Daunorubicin and Daunorubicinol Variables Dnr PK parameters Range (median) DOL PK parameters Range (median) AUC (ng.h/ml) 0.049-2.165 (0.227) 1.311-47.678 (6.812) Clearance (L/hr) 41.561-2014.6 (404.86) 2.30-57.202 (14.99) Volume of distribution (L) 1.6228-266.72 (26.9285) 5.91-286.05 (32.4395) K12 (1/hr) 2.546-31.937 (14.667) 5.82-13.621 (8.416) K21 (1/hr) 0.09-2.766 (0.588) 0.16-0.96 (0.406) Cmax (ng/ml) 30-1863 (126.5) 22-1692 (189.5)
- 41. Daunorubicin plasma pharmacokinetic profile is different in AML relapse patients Pharmacokinetic parameters Relapse p value No (n=29) Median (range) Yes (n=13) Median (range) Dnr AUC (ng.h/ml) 0.31 (0.1-1.74) 0.17 (0.049-2.165) 0.009 DOL AUC (ng.h/ml) 4.99 (1.3-16.5) 8.67 (1.6-20.1) 0.015 Dnr CL (L/hr) 329.31 (42.9-944.5) 546.54 (41.5-1632) 0.011 DOL CL (L/hr) 19.7 (6.1-57) 9.8035 (4.9-56) 0.015 ASH 2014
- 42. Choice and Dosage of Anthracyclines in AML
- 43. Anthracyclines in treatment of AML
- 46. Intermediate risk cytogenetics group HD-DN- High dose Daunorubicin (90mg/m2) SD-DN- Standard dose Daunorubicin (45mg/m2)
- 48. Summary Anthracyclines are one of the potent drugs available to treat various cancers. Brings about its cytotoxic activity by disrupting normal functions of nucleus and mitochondria. Major adverse event is cardiotoxicity Liposomal, pegylated and other formulations of anthracycline are strategies used to avoid cardiotoxicity.
- 49. Thank you…
Editor's Notes
- Good morning. Today I will presenting an overview on anthracyclines, the antitumor antibiotics
- Castle del Monte in Italy was the place from where soil samples were taken and a strain of bacteria which gave out red pigment was identified.
- In the 1950s, Dr. Fedrico Arcamone and Dr Aurelio Di Marco from Farmitalia Research Laboratories in Milan isolated a red pigment which was named as daunorubicin from Streptomyces peucetius. Around the same time daunorubicin was isolated from another strain of Streptomyces in Rhone Poulenc laboratories in France and was named Cerubidine.
- Red aromatic polyketides. Structurally all the anthracyclines share aglyconic and sugar moieties. The aglycone consists of a planar tetracyclic ring. The sugar, daunosamine, is an amino-substituted trideoxyl fucosyl moiety attached to the C-7 of ring A by a glycosidic bond.
- Anthracyclines have been the mainstay in the treatment of various cancers. Especially, Doxorubicin has been used in treatment of various cancers including breast cancer, lung cancer, thyroid cancer, cervical cancer etc. Daunorubicin has been specifically used in treating acute leukemias. Idarubicin which is an analog of daunorubicin is also mostly used in hematological malignancies. Epirubicin is also used in treatment of solid tumors.
- Apart from daunorubicin and doxorubicin there are other anthracyclines such as Aclarubicin, pirarubicin valrubicin are also used in treatment of various cancer. Mitoxantrone which is an anthracenedione antineoplastic drug has been used in treating AML, prostate cancer, breast cancer and non-hodgkins’ lymphoma.
- Coming to mechanism of action,
- In 1964, Dr. Di Marco from Farmitalia lab along with his collegues showed that daunorubicin had remarkable cytotoxic activity at concentrations ranging from 0.01-0.1ug per ml. upon treatment with daunorubicin they could observe that the form and volume of nucleolus, nuclear chromatin, modifications in the chromosomes. Daunorubicin was also found to form complex with the DNA and inhibit synthesis of nuclear RNA.
- Anthracyclines enter the cells by passive diffusion and affect the function of nucleus, mitochonria and cytosol. In the nucleus it intercalates with DNA and also disrupts the function of topoisomerase 2a. In the mitochondria anthracycline semiquinone reacts with mitochondrial DNA, and
- Topoisomerase Iia is a homodimer with three different domains. It is localized in the nucleus and thought to be expressed during the proliferation stage of the cells. The action of topoisomerase II is to bring about reversible double strand breakage and resealing of the break. Daunorubicin stabilizes the double strand break and leads to irrevesible ds break which leads to apoptosis induction
- CBR1 expression was shown as early as 1985 in monocytic leukemic cell lines ML1 and KG1 and was not found to be expressed in K562. Thus in 1995, gonzalez and his group transfected the human CBR cDNa in K562 and showed that the CBR expressing cells had better survival when exposed to daunorubicin than the control cells. Mariann et al in 2007 screened for three enzymes which may be involved in Daunorubicin metabolism and showed that compared to other enzymes CBR1 had 7 fold increased activity than the other enzymes. This proves that CBR is involved in the biotransformation of daunorubicin.
- Moving on tumor microenvironment, several reports have shown that tumor microenvironment is capable of mediating drug resistance due to lesser supply of drug to the niche, altered pH and acidity and hypoxia. In 2010, Luke A Gilbert showed that tumor microenvironment protects cancer cells by release of cytokines such as IL6 and Timp-1 which create a chemo resistant niche that promotes survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse.
- In AML, Matsunaga showed that interaction between VLA4 and fibronectin helped in the survival of leukemic cells in the presence of cytarabine and daunorubicin.
- Numerous reports have shown that miRNA are capable of causing drug resistance in cancer by regulating the protein expression of proteins which are involved in apoptosis and other signalling pathways. In K562 cells it has been shown that miR21 regulates the expression of PTEN which is a tumor suppressor gene and causes daunorubicin resistance. Another miRNA 125b was found to regulate the expression of G protein coupled receptor kinase 2 and knockdown of miR125b made the leukemic cells susceptible to daunorubicin. In breast cancer cells, it was shown that miRNA 451
- With increased exposure to anthracyclines the cardiomyocyte gets injured and with increased period of time these lead to cardiomyopathy and finally heart failure.the major risk factors involve, total cumulative dose, age, femals, concomitant exposure to other neoplastic agents, trisomy 21 and black race.
- The highest accumulation of anthracyclines is seen in the liver, heart white blood cells and bone marrow and once in the heart muscles anthracycline get converted to semiquinone and aglycone derivatives which elicit ROS levels and thus cause mitochondrial DNA damage, energy depletion, impair iron and calcium homeostasis and cause injury to cardiac muscles.
- Down’s syndrome patients have higher chance of developing AML and these patients respond well the therapy with cytarabine and daunorubicin. However, these patients have higher chances of developing cardiotoxicity and it has been shown that use of lower dosage of dnr is sufficient to achieve favourable outcomes without developing cardiotoxicity.
- There are several methods to overcome and prevent anthracycline mediated cardiotoxicity. Slow infusion, use of anti-oxidants, iron chelators and use of various formulations of anthracyclines such as liposomal, pegylated, morpholinyl can help overcome cardiotoxicity.
- Cardiac damage in children with ALL, treated with doxorubicin with or without iron chelator Dexrazoxane were studied. Children treated with the combination had lower cardiac damage than the children treated with doxorubicin alone. Hence iron chelation can be one of the strategies to prevent anthracycline mediated cardiotoxicity.
- Other cardioprotectants which have been described in literature are probucol, N-acetyl cystein. Carvedilol which have anti-oxidant properties Angiotensin converting enzyme inhibitors and Sildenafil which is phospho diesterase 5 inhibitor can also be used to prevent anthracycline mediated cardiotoxicity.
- The pharmacokinetics of anthracyclines is most commonly described as triexponential model
- A small note on choice and dosage of anthracyclines in AML
- This table shows the list of various anthracyclines and their dosages which were used in treating AML. Among the anthracyclines available, daunorubicin has been mostly commonly used in the treatment of AML since 1969. 30mg/m2 for first three days of induction was used and later 45mg/m2 and at present 60mg/m2 of dnr is used.
- Martin Tallman’s group had shown that escalation in daunorubicin dose from 45 to 90mg/m2 was advantageous as patients treated with higher dose had better survival.
- Bob Lowenberg’s group showed that in patients aged 60-65years a dose of 90mg/m2 had better event free survival and overall survival that the patients treated with 45mg/m2
- Similar je-Hwan Lee showed that in intermediate risk group patients treated with 90mg/m2 had better overall survival, relapse free survival and event free survival compared to the patients treated with 45mg/m2.
- In this year’s ASH Dr.Alan Burnett showed that there was not much survival advantage with 90mg/mg/m2 daunorubicin in comparison to 60mg/m2 and 60mg/m2 would be better as toxicities and adverse events will be minimal with lower dosage.