Page 218 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 12 Cancer Chemotherapy 197

This interaction with ribonucleotide reductase can also lead to the Toceranib (TOC) phosphate (Palladia), masitinib (MAS, Kinavet,
allosteric inhibition of other enzymes in the DNA precursor syn- Masivet), and imatinib mesylate (Gleevec) have been used most
350
The mag-
thesis pathway that make up the replitase complex.
commonly in veterinary oncology. At the time of writing, MAS no
VetBooks.ir nitude of decrease in cellular deoxyribonucleotide pools induced longer has Food and Drug Administration (FDA) approval in the
by hydroxyurea treatment correlates with inhibition of DNA syn-
United States, but it remains available in Europe.
thesis observed. 351 Basic Pharmacology. The TKIs used in veterinary oncology
Clinical Pharmacology. HU is dosed orally and distributes inhibit RTKs in the split kinase family. The primary targets of
rapidly to all tissues. Elimination is through hepatic metabolism TOC are KIT (stem cell factor receptor, CD117), vascular endo-
and urinary elimination of the parent compound. AEs associated thelial growth factor receptor 2 (VEGFR2), platelet-derived
with HU treatment include GI effects, myelosuppression (includ- growth factor receptor β (PDGFRβ), and FMS-like tyrosine
ing anemia), and rarely pulmonary fibrosis, with cats being more kinase-3 (Flt-3). 355–357 However, TOC is structurally very similar
susceptible to myelosuppressive effects and potentially methemo- to the human TKI sunitinib, which has been shown to in addi-
globinemia at higher doses. In dogs, a painful detachment of the tion block VEGFR3, PDGFRα, RET, and colony-stimulating
claw (nail) from the quick (onycholysis) is often observed after factor receptor (CSF1R). 358 MAS targets KIT, PDGFR, and Lyn
chronic HU treatment. (an intracellular kinase in the Src family). 359 Imatinib targets KIT,
Clinical Use. HU is used primarily for management of bone Abl, and PDGFR. 360
marrow disorders such as polycythemia vera and granulocytic leu- TOC has a reported oral bioavailability of approximately 80%
kemias. It also has been used to treat canine MCT. 352 HU is safe in dogs and feeding does not affect absorption characteristics. 361
to use at 50 to 60 mg/kg orally once daily initially for 2 weeks fol- TOC is highly protein bound in the plasma (>90%) and under-
lowed by 30 mg/kg/d to lessen myelosuppressive and onycholytic goes hepatic metabolism to a single alicyclic N-oxide metabo-
effects. lite. 362 The half-life of TOC ranges between 13 and 17 hours, and
it is estimated that approximately 90% of TOC and its metabolite
l-Asparaginase are excreted in feces and 10% in urine. 361,362
Basic Pharmacology. The enzymatic function of l-asparaginase Clinical Pharmacology. TKIs can target tumor cells directly by
is the hydrolysis of l-asparagine to l-aspartic acid. This depletion inhibiting normal or mutated RTKs expressed on their surface
of circulating l-asparagine leads to inhibition of protein synthesis that promote cell division and survival. They also can have an anti-
in tumor cells lacking l-asparagine synthetase, causing induction angiogenic effect through inhibition of VEGFR and PDGFR on
of apoptosis. 353 endothelial cells and pericytes, respectively. 355,356
Clinical Pharmacology. l-Asparaginase can be dosed subcuta- AEs likely result from chronic inhibition of RTKs on normal
neously, intramuscularly, or intraperitoneally and blood levels of cells that require these pathways for cell survival and prolifera-
the protein remain for weeks. Hypersensitivity reactions can lead to tion. As to be expected, TKIs that target multiple RTKs often have
a shorter half-life through enhanced clearance. The AEs associated more toxic effects. In both dogs and cats, the most common AEs
with l-asparaginase treatment are a result of either hypersensitiv- associated with TOC and MAS are diarrhea, vomiting, hyporexia,
ity reactions, which may be accentuated after repeated exposures, and less commonly, GI bleeding. 357,363–366 Neutropenia has been
or to decreased protein synthesis from depleted l-asparagine reported with both drugs, but it is relatively uncommon and usu-
pools. 354 Furthermore, neutralizing antibodies may be produced ally mild. Hemolytic anemia has been reported in dogs receiv-
to this foreign protein that can result in limited effectiveness after ing MAS. 363 Protein-losing nephropathies have been reported in
repeated dosing. Hypersensitivity may be managed using pretreat- dogs receiving TOC or MAS, and in cats receiving MAS. 363,366,367
ment antihistamines and occasionally dexamethasone if allergic TOC has also been associated with hypertension in dogs; this AE
reactions are severe enough to warrant its use. Patients receiv- is generally controllable with standard hypertension medications.
ing multiple doses should remain under observation for at least TOC can cause muscle cramping, which usually resolves with
30 minutes after treatment before being discharged, and owners NSAIDs and/or a short drug holiday. 356,357 Imatinib has been
should be advised to observe their pet for 1 to 4 hours after treat- observed to cause idiosyncratic hepatotoxicity in dogs. 356
ment for signs of hypersensitivity. Clinical Use. The label dose for TOC in dogs is 3.25 mg/kg
Clinical Use. l-Asparaginase (400 IU/kg IM or SQ or 10,000 PO q48h. However, subsequent use has shown doses of 2.5 to
IU/m IM or SQ) is used exclusively for lymphoproliferative 2.75 mg/kg either every-other-day or Monday–Wednesday–Fri-
2
disorders. To avoid development of resistance to l-asparginase, day to be effective and better tolerated. 356,368,369 TOC is approved
it is often used only in patients at the time of initial induction for canine MCT. It also has activity against anal sac adenocar-
(especially if clinically ill) or at the time or relapse. A polyethylene cinoma, gastrointestinal stromal tumor, thyroid carcinoma, and
glycol (PEG)ylated form of l-asparaginase is available to mitigate nasal adenocarcinoma. 368,370 In dogs with OSA, the addition of
neutralizing antibody production; however, its use in veterinary TOC-based maintenance protocols after amputation and conven-
medicine is limited because of cost. tional chemotherapy did not improve DFI or survival, although
a small percentage of dogs with gross metastatic OSA do experi-
Targeted Agents ence short-term benefit. 371,372 TOC has been used in cats with a
recommended starting dosage of 2.7 mg/kg Monday, Wednesday,
and Friday, with biologic responses being reported in cats with
Tyrosine Kinase Inhibitors mast cell disease. 364,365
Tyrosine kinase inhibitors (TKIs) are small-molecule inhibitors that The recommended dosage for MAS in dogs is 12.5 mg/kg PO
block, with varying specificity, receptor tyrosine kinases (RTKs) q24h, with a standard dosage reduction to 9.0 mg/kg q24h in
expressed on the cell surface by acting as competitive inhibitors of the event of unacceptable toxicity. 363 It is indicated primarily for
adenosine triphosphate (ATP) binding. ATP binding is required for nonresectable or recurrent MCT. In healthy cats, MAS was well
RTK autophosphorylation and subsequent downstream signaling. tolerated at a dosage of 50 mg (10.9–14.8 mg/kg) PO q48h, 366