Cisplatin is a platinum chemotherapeutic used in a variety of malignancies. The antineoplastic activity occurs from DNA cross-links and adducts, in addition to the generation of superoxide radicals. Nephrotoxicity is the most well-known and potentially most clinically significant toxicity. Unfortunately, the mechanism for cisplatin nephrotoxicity has not been completely elucidated; however, many theories have been developed. Other toxicities include gastrointestinal, myelosuppression, ototoxicity and neurotoxicity. Saline diuresis is currently the most accepted way to prevent cisplatin nephrotoxicity. Research has focused on pharmaceuticals and enzyme/molecular alterations as alternatives to long-term diuresis. No agents have currently been identified that can protect from all toxicities. Cisplatin has shown activity against osteosarcoma, transitional cell carcinoma, squamous cell carcinoma (SCC), melanoma, mesothelioma, carcinomatosis and germinal cell tumours in the dog. In the cat, cisplatin cannot be utilized because of fulminant pulmonary oedema that occurs at standard doses. Intralesional cisplatin has been utilized in horses for the treatment of SCC and sarcoids.
The University of Florida LOPP protocol may be an acceptable alternative to the mechlorethamine, vincristine, procarbazine, and prednisone protocol as a rescue protocol for dogs with lymphoma.
A four-year-old male neutered Australian shepherd dog was diagnosed with a thymoma and concurrent mature T cell lymphocytosis. The lymphocytosis consisted of a mixed population of T cells expressing either CD4 or CD8 or neither marker, and the result of polymerase chain reaction for antigen receptor rearrangement was negative. The peripheral lymphocytosis resolved within 24 hours following thoracotomy and thymectomy. Similar cases have been reported in man, but the aetiology of the increased circulating lymphocytes remains unclear. Although peripheral lymphocytosis is an uncommon paraneoplastic syndrome associated with thymomas, thymoma should be considered as a differential when the increased lymphocytes consist of a mixed population of T cells.
Gunn rats, deficient in the enzyme uridine diphosphate glucuronyl transferase, were used to investigate the effects of unconjugated hyperbilirubinemia in cisplatin nephrotoxicity. The effect of bilirubin on the antineoplastic activity of cisplatin in osteosarcoma cell lines was also determined. The in vivo model involved three groups of rats (n =6 rats/group): homozygous Gunn rats (j/j), heterozygous Gunn rats (j/+), and congenic Wistar rats. On day 0, all rats were given 4 mg/kg cisplatin intraperitoneally. Blood was sampled on days 0, 3, and 5 for bilirubin, BUN, and creatinine and kidneys were taken on day 5. Cell culture was performed in four canine osteosarcoma cell lines using the average concentrations of bilirubin for homozygous Gunn rats at day 0 and 3. Bilirubin was added to cell lines alone and with cisplatin. Cell viability was assessed using the CellTiter Blue assay. Serum bilirubin levels were highly elevated in Gunn j/j, moderately elevated in Gunn j/+, and undetectable in Wistar rats at day 0. Bilirubin provided a nephroprotective effect, with significantly lower BUN and creatinine in Gunn j/j when compared with Wistar rats at day 5. Histological grading demonstrated preservation of the S3 segment in Gunn j/j when compared with Wistar rats (P < 0.05). Bilirubin had no significant effect on the antineoplastic effect of cisplatin at either concentration in the four cell lines (P < 0.001). Hyperbilirubinemia in the Gunn rat provided marked preservation of renal function and histology in a cisplatin nephrotoxicity model. Exogenous bilirubin did not interfere with the antineoplastic activity of cisplatin in vitro.
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