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Lomustine

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

Lomustine is a member of the group of nitrosourea drugs, in their turn classified as alkylating agents. Lomustine is lipophilic and in an aqueous environment breaks down spontaneously into two reactive compounds, one of which is responsible for the alkylation of DNA. After oral administration, it is absorbed and then metabolised in the liver by the microsomal system. Given its liposolubility, lomustine crosses the blood-brain barrier easily. About 50% of the dose administered is eliminated within 24 hours in the urine in the form of metabolites.

 

 

 

 

 

 

 

MECHANISM OF ACTION

Lomustine is a monofunctional alkylating agent and alkylates nucleic acids in position O6 of  guanine. Although it alkylates both DNA and RNA, lomustine does not cross-react with other alkylating agents. Lomustine also inhibits various enzymatic processes.

 

MECHANISM OF RESISTANCE

The main mechanism of resistance involves increased excision of alkylated nucleotides from the DNA chain by 6-alkyl-guanine-transferases (6GT). 6GT removes the alkyl group from position O6 of guanine, thus repairing the DNA and replacing the damaged segment with nucleotides synthesised ex novo.

 

CLINICAL INDICATIONS AND DOSE

In veterinary medicine lomustine is used both as monotherapy and in polychemotherapy for the treatment of multicentric lymphomas (particularly in salvage regimens), cutaneous lymphomas, mast cell tumours, brain tumours and histiocytic sarcomas.

In the dog, the drug is administered orally at a dose of 60-90 mg/m2 every 3-4 weeks (6-8 weeks in the case of brain tumours), without exceeding a cumulative dose of 100 mg.

In the cat, the dose is 50-60 mg/m2per os every 5-6 weeks.

 

TOXICITY

Lomustine can have side effects on the following organs and apparatuses:

  • bone marrow: delayed, dose-dependent, dose-limiting and cumulative myelosuppression (neutropenia and thrombocytopenia). Lomustine should not be given to animals with abnormal white blood cell and platelet counts;
  • liver: in the dog, delayed, dose-dependent and cumulative liver toxicity, sometimes of sudden onset, which can lead to bleeding disorders and biliary cirrhosis. Young dogs, Boxers and subjects with pre-existing raised levels of alanine transaminase are at risk.

·lung: interstitial pneumonia and pulmonary oedema may develop on rare occasions in dogs and cats treated with lomustine. The pulmonary toxicity is worsened by radiotherapy delivered to the anterior half of the body (thoracic region).

 

Suggested readings

  1. 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.
  2. Fan TM, Kitchell BE, Dhaliwal RS et al: Hematological toxicity and therapeutic efficacy of lomustine in 20 tumor-bearing cats: critical assessment of a practical dosing regimen. J Am Anim Hosp Assoc. 2002; 38: 357-63.
  3. Hosoya K, Lord LK, Lara-Garcia A et al: Prevalence of elevated alanine transaminase activity in dogs treated with CCNU (Lomustine)*. Vet Comp Oncol. 2009; 7: 244-55.
  4. Hosoya K, Kisseberth WC, Alvarez FJ et al: Adjuvant CCNU (lomustine) and prednisone chemotherapy for dogs with incompletely excised grade 2 mast cell tumors. J Am Anim Hosp Assoc. 2009; 45: 14-8.
  5. Kristal O, Rassnick KM, Gliatto JM et al: Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs. J Vet Intern Med. 2004; 18: 75-80.
  6. Marconato L: Agenti alchilanti. In: Principi di chemioterapia in oncologia, Marconato (ed), Poletto Editore, 2009: 93-113.
  7. Moore AS, London CA, Wood CA et al: Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J Vet Intern Med. 1999; 13: 395-8.
  8. Rassnick KM, Moore AS, Williams LE et al: Treatment of canine mast cell tumors with CCNU (lomustine). J Vet Intern Med. 1999; 13: 601-5.
  9. Rassnick KM, Gieger TL, Williams LE et al: Phase I evaluation of CCNU (lomustine) in tumor-bearing cats. J Vet Intern Med. 2001; 15: 196-9.
  10. Rassnick KM, Williams LE, Kristal O et al: Lomustine for treatment of mast cell tumors in cats: 38 cases (1999-2005). J Am Vet Med Assoc. 2008; 232: 1200-5.
  11. Risbon RE, de Lorimier LP, Skorupski K et al: Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999-2004). J Vet Intern Med. 2006; 20: 1389-97.
  12. Sauerbrey ML, Mullins MN, Bannink EO et al: Lomustine and prednisone as a first-line treatment for dogs with multicentric lymphoma: 17 cases (2004-2005). J Am Vet Med Assoc. 2007; 230: 1866-9.
  13. Skorupski KA, Clifford CA, Paoloni MC et al: CCNU for the  treatment of dogs with histiocytic sarcoma. J Vet Intern Med. 2007; 21: 121-6.
  14. Skorupski KA, Durham AC, Duda L, Sørenmo KU: Pulmonary fibrosis after high cumulative dose nitrosourea chemotherapy in a cat. Vet Comp Oncol. 2008; 6: 120-5.
  15. Skorupski KA, Rodriguez CO, Krick EL et al: Long-term survival in dogs with localized histiocytic sarcoma treated with CCNU as an adjuvant to local therapy. Vet Comp Oncol. 2009; 7: 139-44.
  16. Williams LE, Rassnick KM, Power HT et al: CCNU in the treatment of canine epitheliotropic lymphoma. J Vet Intern Med. 2006; 20: 136-43.