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Doxorubicin (adriamycin)

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Category: Schede
Hits: 10
  • Disciplina: Oncologia
  • Specie: Cane e Gatto

Doxorubicin (or adriamycin) is an anthracycline and one of the most widely used chemotherapeutic agents in veterinary oncology.

 

CHEMICAL STRUCTURE AND PHARMACOKINETIC PROPERTIES

 

Doxorubicin is an antineoplastic antibiotic that was isolated from Streptomyces peucetius in 1960. The chemical structure is a planar tetracyclic ring, adriamycinone, with a sugar moiety (daunosamine) attached by a glycosidic bond to the A ring of the planar structure. This bond is fundamental for ensuring the drug’s antineoplastic effect. In fact, detachment of the daunosamine renders the tetracyclic ring ineffective from a point of view of tumoricidal activity. Adriamycinone, which gives the compound its characteristic red colour, intercalates between the DNA chains.

The routes of administration of doxorubicin are intravenous, intracavity and intravesical, although this last route of administration has few indications in veterinary medicine. When given intravenously, doxorubicin must be administered diluted in physiological saline over 20 minutes. Bolus administration causes higher plasma peaks, with consequent greater cardiac toxicity. Following intravenous administration, doxorubicin is cleared rapidly from the plasma and binds significantly to tissues. About 70% of the drug is bound to plasma proteins. The passage of the drug across cell membranes occurs through diffusion of non-ionised doxorubicin and through active efflux mediated by glycoprotein p-170. Doxorubicin does not cross the blood-brain barrier. It is metabolised mainly in the liver where it is converted into doxorubicinol, which also has cytotoxic activity. The drug is eliminated mainly in the bile and faeces, while about 10% of the dose administered is excreted through the kidneys. Doxorubicin can be found in the urine for 21 days and in the faeces for 7 days; its levels can no longer be assayed in the serum after 7 days.

 

MECHANISM OF ACTION

The effect of doxorubicin is not dependent on the phase of the cell cycle and the drug exerts its cytotoxic action through three main mechanisms:

  • intercalation, becoming fixed between adjacent bases of DNA by hydrogen bonds, thereby altering the three-dimensional arrangement of DNA, preventing its synthesis and transcription;
  • inhibition of the enzyme topoisomerase II, blocking its catalytic activity;
  • generation of free radicals (superoxides), with consequent damage to intracellular macromolecules, lipid membranes and DNA and RNA bases.

 

MECHANISM OF RESISTANCE

The activity of doxorubicin depends on its capacity to cross cell membranes to reach its target. The rate at which doxorubicin accumulates in tissues, carrying out its cytotoxic activities, is limited by its capacity to leave cells, which in its turn is dependent on active efflux mechanisms of the plasma membrane. These efflux mechanisms confer resistance to several drugs, including doxorubicin, causing the so-called ‘multidrug resistance’(MDR). The transporters responsible for MDR are one-directional transmembrane proteins coded for by ATP-binding cassette (ABC) genes which, by binding to ATP, transport drugs through the membrane from the cytoplasm to the extracellular space. The MDR1 gene can confer a MDR resistance phenotype to neoplastic cells, which thereby become resistant to various chemotherapeutic agents. When over-expressed, MDR1 codes for P-glycoprotein (PgP), the efflux pump that prevents accumulation of chemotherapeutic drugs in neoplastic cells.

 

CLINICAL INDICATIONS AND DOSE

Doxorubicin has a broad spectrum of antineoplastic activity and is indicated for the treatment of haematopoietic malignancies, carcinomas and sarcomas.

The recommended dose as monotherapy in dogs is 30 mg/m2 every 3 weeks for animals weighing more than 10 kg, and 1 mg/kg every 3 weeks for animals weighing less than 10 kg and for cats. The cumulative dose that must not be exceeded is 240 mg/m2 in the dog, and 130-320 mg/m2 in cats. The dose must be reduced in patients with impaired liver function. The optimal duration of treatment has not been established; four to six cycles are usually administered.

 

TOXICITY

Doxorubicin can have side effects on various organs and systems:

 

  • bone marrow: myelosuppression (predominantly neutropenia) is dose-limiting and reversible;
  • gastrointestinal tract: possible nausea, vomiting, loss of appetite to the point of anorexia and haemorrhagic colitis may occur in the dog;
  • skin: hyperpigmentation, reversible alopecia (in dog breeds with continuously growing hair), severe tissue necrosis in the case of extravasation;
  • heart: acute cardiac toxicity is manifested by arrhythmias, which are usually not clinically significant unless there are underlying or pre-existent heart disorders. Chronic toxicity, on the other hand, is serious and irreversible in the dog and is characterized by dilated cardiomyopathy with consequent congestive heart failure. Chronic cardiac doxorubicin-induced toxicity is dose-dependent (240 mg/m2 in the dog) and often results in death. The cause lies in the formation of a Fe3+-doxorubicin complex with subsequent generation of reactive free radicals which lead to oxidative stress in heart muscle. Before every administration, particularly in susceptible breeds (Great Dane, Dobermann) and/or once the cumulative dose has been reached, the fractional shortening should be evaluated by echocardiography; the value should be above 28%. Dexrazoxane, a cardio-protective agent, can prevent dilated cardiomyopathy.
  • hypersensitivity: characterized by cutaneous manifestations (erythema, head shaking, pruritus) (Fig. 1) and gastrointestinal signs (vomiting, diarrhoea) in dogs and respiratory signs (dyspnoea) in cats.
  • renal toxicity: cumulative nephrotoxicity (130-320 mg/m2) in cats.
  • radiation “recall” dermatitis: if administered in a multimodal protocol with radiotherapy, doxorubicin can induce a phenomenon of recall of the cutaneous toxicity induced by the preceding radiotherapy.

 

Suggested readings

 

  1. Ahaus EA, Couto CG, Valerius KD. Hematological toxicity of doxorubicin-containing protocols in dogs with spontaneously occurring malignant tumors. J Am Anim Hosp Assoc. 2000; 36: 422-6.
  2. Astra LI, Hammond R, Tarakji K, Stephenson LW. Doxorubicin-induced canine CHF: advantages and disadvantages. J Card Surg. 2003;18: 301-6.
  3. Baldwin JR, Phillips BA, Overmyer SK, et al: Influence of the cardioprotective agent dexrazoxane on doxorubicin pharmacokinetics in the dog. Cancer Chemother Pharmacol. 1992; 30: 433-8.
  4. Christiansen S, Redmann K, Scheld HH, et al. Adriamycin-induced cardiomyopathy in the dog--an appropriate model for research on partial left ventriculectomy? J Heart Lung Transplant. 2002; 21:783-90.
  5. Chun R, Garrett LD, Vail DM: Cancer chemotherapy. In: Withrow & MacEwen’s Small Animal Clinical Oncology, Withrow SJ and Vail DM (eds), Saunders Elevier, 2007: 163-192.
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  7. Herman EH, Ferrans VJ. Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity. Semin Oncol. 1998; 25: 15-21.
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  11. Mauldin GE, Fox PR, Patnaik AK, et al: Doxorubicin-induced cardiotoxicosis. Clinical features in 32 dogs. J Vet Intern Med. 1992; 6: 82-8.
  12. Ogilvie GK, Richardson RC, Curtis CR, et al: Acute and short-term toxicoses associated with the administration of doxorubicin to dogs with malignant tumors. J Am Vet Med Assoc. 1989; 195: 1584-7.
  13. Ogilvie GK, Reynolds HA, Richardson RC, et al: Phase II evaluation of doxorubicin for treatment of various canine neoplasms. J Am Vet Med Assoc. 1989; 195: 1580-3.
  14. Phillips BS, Kraegel SA, Simonson E, Madewell BR. Acute reactions in dogs treated with doxorubicin: increased frequency with the use of a generic formulation. J Vet Intern Med. 1998; 12: 171-2.
  15. Yeh ET, Bickford CL: Cardiovascular complications of cancer therapy. J Am Coll Cardiol. 2009; 53: 2231-47, 2009.