Doxorubicin

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Doxorubicin (Adriamycin) is one of the anthracycline antibiotics similar to idarubicin and is used as a chemotherapy agent in dogs with lymphoma.

Doxorubicin attacks neoplastic cells via multiple mechanisms, including generation of reactive oxygen species, activating signal transduction pathways, stimulation of apoptosis, and inhibition of protein synthesis by intercalating with DNA and disrupting topoisomerase activity.

Doxorubicin has been used in multidrug regimens such as DAV protocol (doxorubicin, dacarbazine and vincristine combination). With this protocol, doxorubicin and dacarbazine are administered on day 1 while vincristine is administered on days 8 and 15, repeated every 21 days for a maximum of six cycles or until disease progression. This regimen has shown efficacious (50% response rate; 125 day survival) for treatment of canine hemangiosarcoma[1].

The main side-effect with this drug is cardiotoxicity. Irreversible Doxorubicin-associated myocardial failure is a well-recognized problem with this drug and unfortunately, this specific type of heart failure does not respond to the usual medical therapy as other kinds of heart failure[2].

The cardiotoxicity is generally dose and duration dependent[3], but rare patients with multi-drug sensitivity (e.g. Collie) show toxicity at far lower dosages and treatment duration than other dogs. Abnormalities include isolated premature ventricular complexes (which develop in 80% of dogs administered 80 mg/m2/day for 2 days or 25 mg/m2/wk for 4 – 11 wk) and periods of ventricular tachycardia[4].

Myocardial failure may lead to dilated cardiomyopathy, congestive heart failure and sudden death in dogs administered 25 mg/m2/wk for long periods (< 15 weeks).

Fortunately, severe cardiotoxicity is rare with current doxorubicin protocols but dexrazoxane is often used concurrently or following extravasation to prevent cardiotoxicity and extravasation injury[5].

Recommended dose of doxorubicin in dogs is weekly injections for 10 - 13 weeks at 30 mg/m2[6].

References

  1. Dervisis NG et al (2011) Treatment with DAV for advanced-stage hemangiosarcoma in dogs. J Am Anim Hosp Assoc 47(3):170-178
  2. Christiansen S & Autschbach R (2006) Doxorubicin in experimental and clinical heart failure. Eur J Cardiothorac Surg 30(4):611-616
  3. Alves de Souza RC & Camacho AA (2006) Neurohormonal, hemodynamic, and electrocardiographic evaluations of healthy dogs receiving long-term administration of doxorubicin. Am J Vet Res 67(8):1319-1325
  4. Astra LI et al (2003) Doxorubicin-induced canine CHF: advantages and disadvantages. J Card Surg 18(4):301-306
  5. FitzPatrick WM et al (2010) Safety of concurrent administration of dexrazoxane and doxorubicin in the canine cancer patient. Vet Comp Oncol 8(4)':273-282
  6. Zenker I et al (2010) Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma. J Vet Intern Med 26(3):608-613