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Dr. VARUN GOEL
               MEDICAL ONCOLOGIST
RAJIV 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       Idarubicin
Protein         60-70%                      60-70%                 80%                  70-80%
binding
CSF/plasma      Very low                    Very low               Very low             low
ratio
T1/2: ά         40 min.                     10 min                 18.3hr               11.3hr
γ               20-50 hr                    30 hr                  21.1hr               40-60hr



Metabolism      Daunorubicinol,7-           Doxorubicinol          Glucuronides of      13-idarubicinol
                deoxyaglycone               (MC), 7-               parent compd.
                                            deoxyaglycone
Excretion       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%)
administratio
n
Drug           FDA Indication                     Usual Dose                                    Dose Adjustments
Doxorubicin    ALL                                40-60 mg/m2 every 3-4 weeks                   Hepatic dysfunction
               AML                                or
               CLL                                60-75 mg/m2 every 3 weeks
               Kaposi's sarcoma, Non-Hodgkin's
               lymphoma, Mantle cell lymphoma
               Mycosis fungoides, Hodgkin's
               lymphoma, Gastric, Ewing's 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 4
Liposomal      Kaposi's sarcoma                   20 mg/m2 every 3 weeks                        Hepatic dysfunction
doxorubicin    Ovarian                            50 mg/m2 every 4 weeks
Daunorubicin   ALL                                30-45 mg/m2 daily for 3 days                  Renal or hepatic
               AML                                                                              dysfunction
Epirubicin     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 rest
Idarubicin     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.
Duanorubicin        Doxorubicin             Epirubicin          Idarubicin
Dexa, 5-FU ,     Dexa, 5-FU ,            Heparin :           Heparin :
Heparin :        Heparin :               concurrent use      concurrent use
concurrent use   concurrent use          precipitate         precipitate
precipitate      precipitate             formation.          formation.
formation.       formation.
                 Cyclophosphamide:       Cyclophosphamide:   Probenecid : ↑
                 H’ghic                  ↑myelosuppression   risk of uric acid
                 cystitis, Cardiotoxic                       nephropathy
                 ity
                 Phenytoin, gardenal     Cimetidine ↓ AUC
                 : ↑clearance            by 50%
                 Digoxin : decreases
                 bioavail.
                 6-MP:
                 ↑hepatotoxicity
•   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 Heart
Failure as a Function of Cumulative Doxorubicin
Dose
Cumulative Dose          Incidence of Congestive
(mg/m2)                  Heart Failure (%)
<350                   <1

550                    7

600                    15

700                    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                      EFFECTS
ABNORMAL 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
Anthracyclines dr. varun

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Anthracyclines dr. varun

  • 1. Dr. VARUN GOEL MEDICAL ONCOLOGIST RAJIV GANDHI CANCER INSTITUTE, DELHI
  • 2. 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.
  • 3. 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)
  • 4. 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.
  • 5. 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.
  • 6. 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.
  • 7. 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
  • 8.
  • 9. 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.
  • 10. 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.
  • 11. • 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
  • 12. 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.
  • 13.
  • 14. 02 P450 reductase
  • 15. 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.
  • 16. Drug Duanorubicin Doxorubicin Epirubicin Idarubicin Protein 60-70% 60-70% 80% 70-80% binding CSF/plasma Very low Very low Very low low ratio T1/2: ά 40 min. 10 min 18.3hr 11.3hr γ 20-50 hr 30 hr 21.1hr 40-60hr Metabolism Daunorubicinol,7- Doxorubicinol Glucuronides of 13-idarubicinol deoxyaglycone (MC), 7- parent compd. deoxyaglycone Excretion 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%) administratio n
  • 17. Drug FDA Indication Usual Dose Dose Adjustments Doxorubicin ALL 40-60 mg/m2 every 3-4 weeks Hepatic dysfunction AML or CLL 60-75 mg/m2 every 3 weeks Kaposi's sarcoma, Non-Hodgkin's lymphoma, Mantle cell lymphoma Mycosis fungoides, Hodgkin's lymphoma, Gastric, Ewing's 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 4 Liposomal Kaposi's sarcoma 20 mg/m2 every 3 weeks Hepatic dysfunction doxorubicin Ovarian 50 mg/m2 every 4 weeks Daunorubicin ALL 30-45 mg/m2 daily for 3 days Renal or hepatic AML dysfunction Epirubicin 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 rest Idarubicin AML 10-12 mg/m2 daily for 2-3 days Hepatic or renal dysfunction
  • 18. 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.
  • 19. Duanorubicin Doxorubicin Epirubicin Idarubicin Dexa, 5-FU , Dexa, 5-FU , Heparin : Heparin : Heparin : Heparin : concurrent use concurrent use concurrent use concurrent use precipitate precipitate precipitate precipitate formation. formation. formation. formation. Cyclophosphamide: Cyclophosphamide: Probenecid : ↑ H’ghic ↑myelosuppression risk of uric acid cystitis, Cardiotoxic nephropathy ity Phenytoin, gardenal Cimetidine ↓ AUC : ↑clearance by 50% Digoxin : decreases bioavail. 6-MP: ↑hepatotoxicity
  • 20.
  • 21. 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
  • 22. 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.
  • 23. 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.
  • 24. 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.
  • 25. 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
  • 26. 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
  • 27. 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.
  • 28. Incidence of Clinically Detectable Congestive Heart Failure as a Function of Cumulative Doxorubicin Dose Cumulative Dose Incidence of Congestive (mg/m2) Heart Failure (%) <350 <1 550 7 600 15 700 30
  • 29. 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.
  • 30. RISK FACTORS EFFECTS ABNORMAL 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
  • 31. 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.
  • 32. 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.
  • 33. 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)
  • 34. 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.
  • 35. include the use of – angiotensin-converting enzyme (ACE) inhibitors – angiotensin II receptor blockers (ARBs) – carvedilol - has potent antioxidant and anti- apoptotic properties.
  • 36. 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.
  • 37. 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.
  • 38. 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.
  • 39. 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

Editor's Notes

  1. Conjugated cyclic dione structure
  2. Very few drug interactions have been documented for the anthracyclines. Coadministration of heparin and doxorubicin can lead to an increase in the rate of doxorubicin clearance
  3. Liposomes are coated with polyethylene glycol to reduce clearance by mononuclear phagocytes