Dr. VARUN GOEL MEDICAL ONCOLOGISTRAJIV GANDHI CANCER INSTITUTE, DELHI
• In the 1950s, simultaneous efforts by French and Italian researchers led to the development of Daunorubicin.• Daunorubicin was the first of the anthracyclines developed.• Formed by the fermentation products of bacterium Streptomyces peucetius var. caesius and was originally described as antitumor antibiotic.
• The large and growing family of Anthracyclines now includes over 2,000 known analogs.• Derivatives of clinical use are: – Daunorubicin (Cerubidine, Daunomycin, Rubidomycin – Doxorubicin (Adriamycin, Rubex) – Epirubicin (Ellence, Farmorubicin(e), Farmorubicina, Pharmorubicin) . – Idarubicin (Idamycin, Zavedos) – Amrubicin (Calced) – Esorubicin – Aclarubicin (Aclacinomycin) – Pirarubicin. – Valrubicin (Valstar)
• These compounds consist of: – Planar Hydrophobic tetracycline ring – Daunosamine sugar linked through a glycosidic linkage.• All drugs are positively charged at physiologic pH, favoring intercalation into DNA.• Anthracyclines possess Quinone moieties on adjacent rings : Allow them to participate in electron transfer reactions and generate oxygen free radicals.
• Daunomycin and doxorubicin differ only by a single hydroxyl at position C14, yet have distinct spectra of antitumor activity.• Idarubicin is a semisynthetic derivative of daunomycin (4-demethoxydaunorubicin) lacking the 4-methoxy group present on the parent compound.• Epirubicin is an epimer of doxorubicin having the C4′ hydroxyl group on the amino sugar in the equatorial rather than the axial position. This increases lipophilicity compared with doxorubicin.
• Cell cycle nonspecific (predominant action on G2/S phase) of cell cycle.• Various mechanisms are implicated for its cytotoxicity: – DNA intercalation. – Inhibition of topoisomerase II – Formation of cytotoxic oxygen free radical.
• Intracellular drug concentrated in the nucleus• Anthracycline in the nucleus is intercalated into the DNA double helix.• The consensus sequence for highest doxorubicin affinity is 5´-TCA.• It is the planar ring, which actually intercalates into DNA and the side chain provides an important hydrogen-bonding function.• Intercalation prevents replication of rapidly growing cancer cells
• DNA topoisomerases are a general class of enzymes that alter the topology of DNA.• Found in all organisms, including Archaebacteria, viruses, yeast, Drosophila, and humans.• Access to DNA during processes such as replication, transcription, and recombination requires double-helical DNA to be separated, resulting in torsional stress.• There are two general classes of topoisomerases; type I and type II, distinguished by the number of DNA strand breaks they make during catalysis.
• Top1 is important in supporting replication fork movement during DNA replication and to relax supercoils generated during transcription.• Top2 is responsible for: – unlinking intertwined daughter duplexes during DNA replication – contributes to DNA relaxation during transcription – facilitates remodeling of chromatin structure.• Type II topoisomerase enzymes function as homo- or heterodimers and require adenosine triphosphate for catalysis.
• A Topoisomerase dimer binds to DNA, forming a double-strand DNA break in which the proteins are covalently bound to the 5´ end of broken DNA strands to form the Top2 cleavable complex.• Forms a gate in the DNA through which a second DNA double- helix strand can pass in an energy-dependent fashion.• Anthracyclines poison Top2 by stabilizing the DNA-Top2 cleavable complexes, leading to DNA double-strand breaks
• Main mechanism of generating O2 Free Radical is one-electron reduction of the Anthracyclines’ quinone side rings.• Catalyzed by Flavin-centered dehydrogenases, including cytochrome P-450 reductase, NADH dehydrogenase (complex I of the mitochondrial electron transport chain), xanthine oxidase, and cytochrome B5 reductase.• Cause widespread damage to intracellular macromolecules, including lipid membranes, DNA bases, and thiol-containing transport proteins.
02 P450 reductase
• Resistance to topoisomerase-targeting drugs can involve alterations in • drug accumulation, • Increased expression of the multidrug –resistant(MDR) gene with elevated P-170 levels leading to drug efflux• Decreased expression of Topoisomerase II.• Mutation in Topoisomerase II with decreased binding affinity to drug.• Increased expression of sulphydryl proteins including glutathione reductase.
Drug Duanorubicin Doxorubicin Epirubicin IdarubicinProtein 60-70% 60-70% 80% 70-80%bindingCSF/plasma Very low Very low Very low lowratioT1/2: ά 40 min. 10 min 18.3hr 11.3hrγ 20-50 hr 30 hr 21.1hr 40-60hrMetabolism Daunorubicinol,7- Doxorubicinol Glucuronides of 13-idarubicinol deoxyaglycone (MC), 7- parent compd. deoxyaglyconeExcretion Biliary (70%), Biliary (50%), Renal Biliary (60-70%), 80% renal Renal(<20%) (<10%) renal (20%)Toxicity Myelosuppression,muc Myelosuppression, Leukopenia Leukopenia ositis, aloplecia,cardiac mucositis, Thrombocytopenia Thrombocytopenia toxicity, vesicant aloplecia,cardiac , , toxicity, vesicant cardiotoxicity(=do cardiotoxicity(<do xorubicin) xorubicin)Route of Intravenous (i.v.) i.v. i.v. i.v., oral(30%)administration
Drug FDA Indication Usual Dose Dose AdjustmentsDoxorubicin ALL 40-60 mg/m2 every 3-4 weeks Hepatic dysfunction AML or CLL 60-75 mg/m2 every 3 weeks Kaposis sarcoma, Non-Hodgkins lymphoma, Mantle cell lymphoma Mycosis fungoides, Hodgkins lymphoma, Gastric, Ewings sarcoma Prostate, Thyroid Nephroblastoma Neuroblastoma Non-small cell lung Ovarian Transitional cell bladder Cervical 30 mg/m2 Langerhans cell 50 mg on days 1 and 22 every 42 days Multiple myeloma 9 mg/m2 continuous infusion days 1 to 4Liposomal Kaposis sarcoma 20 mg/m2 every 3 weeks Hepatic dysfunctiondoxorubicin Ovarian 50 mg/m2 every 4 weeksDaunorubicin ALL 30-45 mg/m2 daily for 3 days Renal or hepatic AML dysfunctionEpirubicin Breast 100-120 mg/m2 every 3-4 weeks Hepatic or renal or dysfunction 60 mg/m2 weekly for 2 weeks followed by 1-2 weeks restIdarubicin AML 10-12 mg/m2 daily for 2-3 days Hepatic or renal dysfunction
Amrubicin, a fully synthetic 9-amino anthracycline, is approved and marketed in Japan for the treatment of lung cancer. A recent randomized phase 2 study found that amrubicin was superior to topotecan in 60 relapsed small cell lung cancer patients in terms of response rates. Additional anthracyclines are in clinical development including aclarubicin, valrubicin, and zorubicin. All appear to share a similar mechanism of action in terms of topoisomerase 2 poisoning.
• Common side effect in all Anthracyclines.• Special considerations are necessary• Chronic cardiotoxicity is the most common type of anthracycline damage.• The prevalence of late subclinical cardiac damage has been reported to be more than 57% at a median of 6.4 years after treatment among survivors of childhood cancers .• The incidence of clinical heart failure as high as 16%, 0.9 to 4.8 years after treatment.• Differences in study population, treatment protocols, and duration of follow-up could account for this wide variability Ann Oncol 2002
Can be divided into:• Acute or Subacute: Heart damage that develops immediately after the infusion of the drug or within a week of therapy.• Early onset chronic progressive cardiotoxicity: a depression of myocardial function which occurs during the treatment or within the first year after treatment.• Late onset chronic progressive cardiotoxicity: this occurs at least 1 year after the end of treatment.• Acute doxorubicin cardiotoxicity is reversible but chronic is irreversible.
• Early Cardiotoxicity: Myocarditis-pericarditis.• Early cardiotoxicity is presumably related to myocyte damage or death resulting in depressed left ventricular contractility.• Chronic cardiotoxicity: Cardiomyopathy - -Myofibrillar loss -vacuolar degeneration and coalescence of the sarcotubular system related to myocyte damage or death resulting in depressed left ventricular contractility & decreased left ventricular systolic function.• Chronic cardiotoxicity peaks at 1 to 3 months, but can occur even years after therapy.
Myocardial damage occurs by several mechanisms, the most important is generation of reactive oxygen species during electron transfer from the semiquinone to quinone moieties of the anthracycline. The generation of hydrogen peroxide and the peroxidation of myocardial lipids contribute to myocardial damage. Endomyocardial biopsy is characterized by a predominant finding of multifocal areas of patchy and interstitial fibrosis (stellate scars) and occasional vacuolated myocardial cells (Adria cells). Myocyte hypertrophy and degeneration, loss of cross-striations, and absence of myocarditis are also characteristic of this diagnosis.
Other suggested cardiotoxicity mechanisms include: metabolism of ANT into more hydrophilic and cardiotoxic substances, which subsequently accumulate in cardiomyocytes impaired expression of various important cardiac proteins disruption of cellular and mitochondrial Ca2+ homeostasis induction of mitochondrial DNA lesions disruption of mitochondrial bioenergetics degradation of myofilamental and cytoskeletal proteins, including titin and dystrophin interference with various pro-survival kinases
predisposition to cardiac damage includes a previous history of heart disease, hypertension, radiation to the mediastinum, age younger than 4 years, prior use of anthracyclines or other cardiac toxins, and coadministration of other chemotherapy (e.g., paclitaxel, cyclophosphamide, or trastuzumab). Sequential administration of paclitaxel followed by doxorubicin in breast cancer patients is associated with cardiomyopathy at total doxorubicin doses above 340 to 380 mg/m2, whereas the reverse sequence of drug administration did not yield the same systemic toxicities
The incidence of cardiomyopathy is related to both cumulative dose and schedule of administration. Cardiac toxicity is best correlated with peak plasma concentration of the parent drug rather than with the AUC. Greater cumulative doses of doxorubicin can be given to patients receiving low-dose continuous infusions than to those receiving higher-dose bolus injections every 3-4 weeks.
Incidence of Clinically Detectable Congestive HeartFailure as a Function of Cumulative DoxorubicinDoseCumulative Dose Incidence of Congestive(mg/m2) Heart Failure (%)<350 <1550 7600 15700 30
Clinically detectable congestive heart failure when doxorubicin is given at doses of 40-75 mg/m2 as a bolus injection every 3-4 weeks. But when doxorubicin is given by a low-dose weekly regimen (10-20 mg/m2/wk) or by slow continuous infusion over 96 h, cumulative doses of more than 500 mg/m2 can be given. Doses of epirubicin below 1,000 mg/m2 and daunorubicin below 550 mg/m2 are considered safe. Doses of idarubicin below 290 mg/m2 do not produce clinical congestive heart failure despite changes in cardiac ejection.
RISK FACTORS EFFECTSABNORMAL CARDIAC FUNCTION INCREASE CUMULATIVE DOSE INCREASE AGE Children <5 yr increased risk SEX FEMALE SEX INCREASED RISK IRRADIATION INCREASE ADDITIONAL TREATMENT Co T/t WITH CYCLO/PACLITAXEL/TRASTUZUMA B/BLEOMYCIN BLACK RACE INCREASE TRISOMY21 INCREASE LENGTH OF FOLLOW UP INCREASE LENGTH OF INFUSION DECREASE
Efforts in this direction have so far focused on: Dose and formulation of the anthracyclines. Development of safe new derivatives. Simultaneous treatment with protective substances thought to interact beneficially.
Liposomal formulations are said to promote tumor concentrations of the drug while exposing normal tissue to lower, at best non toxic levels. They are also associated with higher rates of other toxic effects such as neutropenia Furthermore, these formulations are extremely expensive and so far lack evidence on long term safety or harms.
Newer anthracyclines• tumor activated anthracycline "prodrugs” such as pirarubicin and valrubicin and N-L- leucyl-doxorubicin.• unable to penetrate healthy cells, but are activated and potentiated extracellularly by tumor secreted peptidases.• Disaccharide derivatives of anthracyclines are known as third generation anthracyclines. The best known is sabarubicin or MEN 10755.(PH 2 trials)
The iron chelating agent dexrazoxane, reduce anthracycline induced oxygen radical production.• Dexrazoxane(dex) is FDA approved to prevent anthracycline induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin(dox) of 300 mg/m2 & would benefit from continued treatment.• Recommended dose is to give dexrazoxane I.V. 30 minutes before doxorubicin at a ratio of dex:dox of 10:1.
• include the use of – angiotensin-converting enzyme (ACE) inhibitors – angiotensin II receptor blockers (ARBs) – carvedilol - has potent antioxidant and anti- apoptotic properties.
• Important dose limiting toxicity .• Leucopenia more common than thrombocytopenia and anemia.• Myelosuppression begins in 7 days following administration.• Nadir occurs by day 10-14 followed by recovery by day 21.• Thrombocytopenia and anemia less severe.• Daunorubicin : BM suppression > mucositis• Doxorubicin :BM suppression= mucositis.• Growth factor support often needed .• With weekly dosing or continuous infusion, mucositis frequently becomes the dose-limiting toxicity.
• Extravasation of most anthracyclines leads to severe local injury that can continue to progress over weeks to months.• The drug has been shown to bind locally to tissues• Local wound care to prevent infection is most important.• A wide range of treatments including ice, steroids, vitamin E, DMSO(dimethyl sulphoxide), and bicarbonate used.• Recently cardioprotectant Dexrazoxane has been used to treat acute Anthracycline extravasations in combination with subcutaneous granulocyte- macrophage colony-stimulating factor to promote wound healing.
Nausea & vomiting. Hyperpigmentation of nails , urticaria. Aloplecia Red orange color of urine . Lasts 1-2 days after drug administration. Erythema at injection site – flare reaction. RADIATION RECALL. increased inflammation in previously irradiated areas can lead to pericarditis, pleuritis and skin rashes.
• RISK OF SECONDARY MALIGNANCY:• Anthracyclines are also known to multiply the risk of developing acute myelogenous leukemia, a form of leukemia which is usually unresponsive to treatment and carries a poor prognosis.• Overall absolute risk remains low (estimated at less than 2% at ten years after treatment) JCO 2002