Page 214 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 12 Cancer Chemotherapy 193

cumulative nephrotoxicity 217 and should be used cautiously in these agents are generally analogs of compounds used in the
cats with underlying renal disease, with close monitoring of renal normal course of metabolism and in the case of cancer chemo-
therapeutics, specifically anabolic processes associated with DNA
function parameters.
VetBooks.ir a wide variety of cancers in companion animals. The drug may be replication.
Clinical Use. DOX is the most active single agent available for
used alone or in combination protocols for a variety of cancers Cytosine Arabinoside
including lymphoma, HSA, OSA, histiocytic sarcoma, feline ISS, Basic Pharmacology. Cytosine arabinoside (cytarabine, Ara-C)
mammary carcinoma, thyroid carcinoma, and colonic adenocar- acts as an analog to deoxycitidine and is phosphorylated in cells
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cinoma. Conventional dosing regimens are 30 mg/m via IV infu- to generate arabinosylcytosine triphosphate (ara-CTP), which acts
sion (15–30 minutes) every 3 weeks in dogs larger than 15 kg, as a competitive inhibitor of DNA polymerase α. 239 Ara-CTP is
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and either 25 mg/m or 1 mg/kg for dogs smaller than 15 kg and also incorporated into DNA, which correlates with cytotoxic-
all cats. ity, 240 and thus presumably is the primary mechanism of action.
Incorporation into DNA cannot be excised 241 and inhibits both
Mitoxantrone the function of the DNA template and subsequent synthesis. 242
Basic Pharmacology. Mitoxantrone (MTO) is a synthetic Ara-C has also been reported to have a differentiating function
DOX analog and maintains similar activity as DOX in terms of in leukemic cells through decreased c-myc expression. 243 Ara-C
DNA intercalation and the inhibition of RNA and DNA poly- is actively transported into tumor cells via nucleoside transport-
merases and topoisomerase II. 218,219 However, MTO does not ers 244 and phosphorylated sequentially by deoxycytidine kinase,
cause oxidative damage to cells 220 and has a reduced potential to dCMP kinase, and nucleoside diphosphate kinase. 245
undergo one-electron reduction and generate ROS. 221 Clinical Pharmacology. Ara-C is water-soluble and dosed by
Clinical Pharmacology. After IV administration, MTO is intravenous infusion. It distributes rapidly in total body water and
extensively distributed to tissues, with residual levels being long crosses into the central nervous system (CNS) with cerebrospinal
lasting. MTO is not extensively metabolized and a fraction of the fluid concentrations reaching approximately 60% of plasma lev-
drug (<30%) is excreted unchanged in the urine and feces. 222– els at steady-state. 246 The primary mode of metabolism is deami-
224 The DLT is myelosuppression. Cardiotoxicity has not been nation by the liver and extrahepatic tissues. Observed DLTs are
reported in dogs and only rarely in humans. myelosuppression and occasionally GI signs.
Clinical Use. MTO is administered at a dose of 5.0 to 5.5 mg/ Clinical Use. Ara-C is administered at a dose of 600 mg/m ,
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m in dogs and 6 mg/m in cats as a slow IV bolus every 3 weeks. ideally as a CRI over a 2- to 5-day duration. However, a more con-
It is considered a front-line drug for treating canine TCC and venient method of administration in dogs and cats is to divide that
anal sac adenocarcinoma. 225,226 MTO has been used as a cardiac- dose into 4 SC injections given twice daily for 2 consecutive days.
sparing alternative to DOX in dogs with underlying myocardial Ara-C was not effective as a single agent at inducing remission in
dysfunction or that have reached their maximum cumulative dose naïve canine lymphoma, 247 but is a component of the rescue protocol
of DOX with the potential for similar outcomes, 227 and as a rescue DMAC (dexamethasone, melphalan, actinomycin-D, Ara-C). 248
agent in relapsed canine lymphoma with mixed results. 228 However, results of a recent small study suggest improved
responses in dogs with naïve, stage V multicentric lymphoma
Actinomycin D (Dactinomycin) when Ara-C (150 mg/m /day as a continuous rate infusion) was
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Basic Pharmacology. Actinomycin D, or dactinomycin infused over 5 days after the first and second cycle of a conven-
(DACT), consists of two symmetric polypeptide chains attached tional CHOP-based protocol compared with the CHOP protocol
to a central phenoxazone ring. DACT has been shown to interact alone. 249 Bone marrow support with human granulocyte colony
with double-stranded DNA in multiple ways in a sequence-depen- stimulating factor and erythropoietin were coadministered with
dent manner, 229–231 and also bind to single-stranded DNA. 232 The Ara-C and patients in this treatment group did not experience
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resulting interactions of DACT with both double- and single- increased AEs. Low-dose subcutaneous Ara-C (50 mg/m BID for
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stranded DNA results in a potent inhibition of transcription, thus 2 days or 100 mg/m as a constant rate infusion for 1 day) has been
inhibiting RNA and protein synthesis. 233,234 DACT is taken up reported to improve clinical signs in dogs with meningoencepha-
into cells by passive diffusion, 235 and the sensitivity of cells may litis of unknown origin when combined with prednisone. 250,251
depend on uptake and retention, 236 with ABCB1 playing a role in
DACT efflux. 237 Methotrexate
Clinical Pharmacology. After IV administration, DACT is rap- Basic Pharmacology. Methotrexate (MTX) is a folate analog
idly distributed to tissues and then slowly eliminated from tissues. that inhibits the enzyme dihydrofolate reductase, thus depleting
Metabolism is minimal, with 20% of DACT excreted unchanged reduced folate pools required for purine and thymidylate biosyn-
in the urine and 14% in the feces. 238 The major DLTs of DACT thesis. 252 MTX is also converted to polyglutamates that act as
are myelosuppression and GI toxicity. 238 It is a vesicant and can direct inhibitors of folate-dependent enzymes that play a role in
cause severe tissue damage if extravasated. de novo purine and thymidylate synthesis. 253,254 MTX enters cells
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Clinical Use. DACT is used in multiagent protocols for dogs via active transport through the reduced folate carrier.
with lymphoproliferative diseases in the relapse setting or as a Clinical Pharmacology. The oral bioavailability of MTX is
DOX substitute in dogs with cardiac abnormalities. It is adminis- high at lower doses but becomes variable as doses increase, 255 and
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tered IV at 0.5–0.75 mg/m every 1–3 weeks. thus is usually dosed orally at lower doses and intravenously at
higher doses. The PK of MTX is well understood across species 256
Antimetabolites and is dominated by enterohepatic recycling that accounts for the
observed GI side effects at doses that do not cause hematopoietic
The antimetabolites comprise agents that inhibit the use of cellu- toxicities. At higher doses, both GI toxicity and myelosuppres-
lar metabolites in the course of cell growth and division. Therefore sion are observed. MTX does not undergo substantial hepatic