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Cisplatin

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Category: Schede
Hits: 12
  • Disciplina: Oncologia
  • Specie: Cane e Gatto

Cisplatin is a chemotherapeutic agent used for the treatment of various malignancies in the dog. It is defined as an alkylating-like agent (rather than an alkylating one), because it does not contain alkyl groups and does not cause alkylation reactions. Cisplatin is considered one of the most effective chemotherapeutic drugs for the treatment of solid tumours in both humans and dogs.

 

CHEMICAL STRUCTURE AND PHARMACOKINETIC PROPERTIES

Cisplatin has a square planar geometry with a platinum atom at the centre coordinated with two chlorine atoms and two ammonia molecules in cis on the horizontal plane. In an aqueous environment, the chlorine atoms are replaced by hydroxyl groups and, then, by bases of DNA. If there is a high concentration of chloride in the environment, the substitution reaction does not occur readily and the cisplatin remains neutral. For this reason, cisplatin diluted in fluids such as blood and extracellular fluid, which are rich in chloride atoms, is not activated prematurely and penetrates easily into the neoplastic cells. In contrast, if there is a low concentration of chloride in the environment, cisplatin becomes reactive. This is the case in intracellular fluid, in which cisplatin undergoes substitutions and then reactions with nucleophilic groups. After intravenous administration, 90% of the drug present in the blood is bound to plasma proteins. Tissue distribution is fast. The plasma cisplatin levels have a biphasic time course with a first half-life of 22-50 minutes and a second half-life of 3-5 days. Elimination in the urine is initially rapid, but then slow and incomplete. The straight part of the proximal tubules is most involved in the secretion of cisplatin and is, therefore, the tissue most affected by toxicity. Fifteen percent of cisplatin is eliminated unmodified. Some of the drug accumulates and persists in tissues for prolonged periods.

 

MECHANISM OF ACTION

Cisplatin forms inter-chain and intra-chain cross-links in DNA, inducing apoptosis of the affected cells. In fact, once the DNA has been damaged, repair mechanisms are triggered, but cannot be completed thus causing death of the cells. The action of cisplatin is not dependent on the phase of the cell cycle.

 

MECHANISM OF RESISTANCE

The main mechanisms responsible for resistance of neoplastic cells to cisplatin are alterations in the transport and/or reduced accumulation of cisplatin within the cell, increased efflux and more efficient mechanisms of repairing the DNA damage caused by cisplatin.

 

CLINICAL INDICATIONS AND DOSE

 

 

Cisplatin is used in dogs both as single agent therapy and in polychemotherapeutic regimens for the treatment of osteosarcomas, melanomas, ovarian carcinomas, urothelial carcinomas, mesotheliomas, squamous cell carcinomas, nasal carcinomas, thyroid carcinomas, carcinomas of the tonsil and, in general, inhigh-grade carcinomas and sarcomas.

Cisplatin can be administered intravenously or topically (slow-release implants) or into body cavities. The dose for intravenous administration is 50-70 mg/m2 every 3 weeks, together with a  6-hour diuresis protocol with physiological saline (20 ml/kg/hour). Cisplatin is fatal in cats and should not be given to these animals.

 

TOXICITY

Cisplatin can have side effects on the following organs and biological structures:

  • kidneys: cumulative, dose-dependent, dose-limiting nephrotoxicity, which tends to become irreversible. The preferential target of the nephrotoxicity is the straight part of the proximal tubule. Dogs should be hydrated before, during and after administration of cisplatin in order to minimise the nephrotoxicity. Furthermore, before the first treatment and before every subsequent administration, renal function and electrolytes must be monitored in order to pick up low serum levels of magnesium and calcium, if present. These electrolyte disorders may occur as a result of urinary loss of magnesium and calcium due to a drug-induced impairment of tubular reabsorption.
  • bone marrow: myelosuppression.
  • gastrointestinal tract: emesis, which characteristically peaks within 24 hours and then peaks again between the second and fourth day of treatment. An anti-emetic (butorphanol, maropitant, ondansetron) should be given before treatment with cisplatin and for the following few days.
  • ear: cumulative, dose-dependent and irreversible ototoxicity.
  • respiratory tract: cisplatin is fatal in cats, as it causes severe hydrothorax, pulmonary and mediastinal oedema and death within 48-96 hours.

AnchorAnchor

Careful evaluation of the renal function and good hydration of the patient are necessary in order to prevent cisplatin-associated nephrotoxicity. Various protocols for hydration, associated or not with the concomitant administration of furosemide have been demonstrated to be useful in reducing nephrotoxicity. The dog is normally hydrated before, during and after administration of cisplatin, using a physiological saline solution. The fluid is infused over 4-6 hours, depending on the protocol and the patient’s cardiocirculatory condition.

Diuresis protocols that can be used in the dog:

  • 3 hours of diuresis PRE-cisplatin, 1 hour of diuresis POST-cisplatin, infusion rate 25 ml/kg/hour
  • 4 hours of diuresis PRE-cisplatin, 2 hours of diuresis POST-cisplatin, infusion rate 18.3 ml/kg/hour
  • 3 hours of diuresis PRE-cisplatin, 3 hours of diuresis POST-cisplatin, infusion rate 20 ml/kg/hour

 

Suggested readings

  1. Barabas K, Milner R, Lurie D, Adin C: Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol. 2008; 6: 1-18.
  2. Daugaard G, Abildgaard U, Holstein-Rathlou NH et al: Acute effect of cisplatin on renal hemodynamics and tubular function in dog kidneys. Ren Physiol. 1986; 9: 308-16.
  3. Daugaard G, Abildgaard U, Larsen S et al: Functional and histopathological changes in dog kidneys after administration of cisplatin. Ren Physiol. 1987; 10: 54-64.
  4. Daugaard G, Abildgaard U, Holstein-Rathlou NH et al: Effect of cisplatin on renal haemodynamics and tubular function in the dog kidney. Int J Androl. 1987; 10: 347-51.
  5. de la Puente-Redondo VA, Tilt N, Rowan TG, Clemence RG: Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs. Am J Vet Res. 2007; 68: 48-56.
  6. Klein J, Bentur Y, Cheung D et al: Renal handling of cisplatin: interactions with organic anions and cations in the dog. Clin Invest Med. 1991; 14: 388-94.
  7. Knapp DW, Richardson RC, DeNicola DB et al: Cisplatin toxicity in cats. J Vet Intern Med. 1987; 1: 29-35.
  8. Lelieveld P, van der Vijgh WJ, van Velzen D: Preclinical toxicology of platinum analogues in dogs. Eur J Cancer Clin Oncol. 1987; 23: 1147-54.
  9. Marconato L: Sali del platino. In: Principi di chemioterapia in oncologia, Marconato (ed), Poletto Editore, 2009: 114-122.
  10. Ogilvie GK, Moore AS, Curtis CR: Evaluation of cisplatin-induced emesis in dogs with malignant neoplasia: 115 cases (1984-1987). J Am Vet Med Assoc. 1989; 195: 1399-403.
  11. Ogilvie GK, Straw RC, Powers BE et al: Prevalence of nephrotoxicosis associated with a short-term saline solution diuresis protocol for the administration of cisplatin to dogs with malignant tumors: 61 cases (1987-1989). J Am Vet Med Assoc. 1991; 199: 613-6.
  12. Pendyala L, Cowens JW, Creaven PJ: Studies on the pharmacokinetics and metabolism of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) in the dog. Cancer Treat Rep. 1982; 66: 509-16.
  13. Sockalingam R, Filippich L, Charles B, Murdoch B: Cisplatin-induced ototoxicity and pharmacokinetics: preliminary findings in a dog model. Ann Otol Rhinol Laryngol. 2002; 111: 745-50.