58° Congresso Nazionale SCIVAC: Oncologia veterinaria

58° Congresso Nazionale SCIVAC • Milano, 7-9 Marzo 2008 • Oncologia veterinaria - Alle soglie del III Millennio
TOPOISOMERASE INHIBITORS
Are drugs that interact with the physical structure and activity of DNA both
in the production of RNA and replication of DNA. These drugs are typically natural
products that inhibit the DNA unwinding enzyme topoisomerase.
DOXORUBICIN
Doxorubicin was discovered in Italy as an anthracycline antibiotic derivative
of a soil fungus.
Mechanism of action
Doxorubicin is a particularly potent antineoplastic drug in part because it
has several different actions that can result in cell death. Doxorubicin intercalates
DNA, and by virtue of the presence of quinone and hydroquinone side
chains can for covalent cross-links. The presence of doxorubicin in the DNA
chain impairs DNA synthesis, RNA synthesis, topoisomerase activity, and helicase
activity. Doxorubicin is capable of causing iron-mediated free-radical
formation, which in turn leads to lipid peroxidation and cell membrane effects.
Mechanism of drug resistance is largely through activation of the P-
glycoprotein cell membrane pump. P-glycoprotein activity results in inability
of the doxorubicin to insert itself into nuclear DNA.
Pharmacokinetics
Doxorubicin is administered intravenously at doses of 30 mg/m 2 body surface
area in dogs or 1 mg/kg dose in cats and small dogs. Doxorubicin undergoes
extensive biotransformation in the liver to active and inactive metabolites.
The drugs is extensively protein abound in plasma and tissues and is
excreted almost exclusively in bile in animal species.
Toxicity
In addition to having the broadest spectrum of activity of any of the commonly
used antineoplastic drugs, doxorubicin also has perhaps the widest profile
of commonly seen significant toxicities. Myelosuppression, gastrointestinal
signs (particulary nausea, vomiting and colitis), and alopecia are all seen in pa-
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