Page 215 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

194 PART 3 Therapeutic Modalities for the Cancer Patient

metabolism except when administered at high doses and is pri- Clinical Pharmacology. 5-FU is dosed IV and is extensively
marily excreted unchanged in the urine. 256 metabolized in many tissues by dihydropyrimidine dehydrogenase
to dihydrofluorouracil, which is further catabolized to α-fluoro-
Clinical Use. MTX was used in original multiagent protocols
VetBooks.ir for treatment of lymphoproliferative disorders in dogs and cats. β-alanine, ammonia and CO . 281,282 Approximately 90% of an
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With the development of other less toxic and more potent agents,
administered dose is metabolized, and both 5-FU and its catabo-
MTX has been eliminated from conventional treatment regimens lites undergo biliary excretion with <5% of the parent drug renally
and is rarely used in veterinary oncology. excreted. 5-FU causes a dose-dependent myelosuppression, GI
toxicity, and neurotoxicity in dogs. Inadvertent ingestion of a top-
Gemcitabine ical 5-FU cream is toxic and/or fatal. 283 5-FU is contraindicated
Basic Pharmacology. Gemcitabine (GCB), or 2,2-difluo- in cats because of severe CNS toxicity.
rodeoxy‒cytidine (dFdC), is actively transported into cells by Clinical Use. 5-FU is infrequently used for management of
nucleoside transporters 257 and metabolized by phosphorylation organ epithelial tumors (hepatic, pancreatic, renal, mammary).
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to mono- (dFdCMP), di- (dFdCDP), and triphosphorylated The reported dose is 150 mg/m IV weekly. It also may be admin-
(dFdCTP) species. 245 The effect of dFdC treatment on cells is istered topically and intralesionally to dogs, although convincing
the inhibition of DNA synthesis through dFdCTP inhibition reports of efficacy are not available.
of DNA polymerase, 258 dFdCDP inhibition of ribonucleotide
reductase and subsequent depletion of deoxyribonucleotide Rabacfosadine (Tanovea)
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pools, and dFdCTP incorporation into DNA leading to strand Basic Pharmacology. Rabacfosadine (RFD) is a multiactiva-
termination. The dFdCTP incorporated into newly synthesized tion-step prodrug that results in the intracellular generation of
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DNA appears resistant to normal DNA repair 259 and its presence the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine
is critical for triggering apoptosis by this agent. 260 Recent studies (PMEG). 284 The metabolic sequelae of RFD involve cellular
suggest that the primary deamination metabolite of dFdC, dFdU, uptake of the parent compound and subsequent hydrolysis by
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may also play a role in cytotoxicity. 261 cathepsin A to cPrPMEDAP and deamination by N -methyl-AMP
Clinical Pharmacology. GCB is dosed intravenously because aminohydrolase to generate intracellular PMEG. 285–287 PMEG is
oral dosing leads to low systemic exposure, 262 presumably then phosphorylated to the diphosphate form (PMEGpp) that
because of extensive first-pass metabolism in the liver through competes with dGTP as a substrate for DNA polymerases with
deamination to the dFdU metabolite. 263 Infusion length also resulting incorporation into DNA resulting in chain termina-
seems to be a potentially important variable as longer, constant tion. 288,289 Distribution studies of RFD have shown preferential
rate infusions have been shown to lead to increased intracellu- uptake into PBMCs and lymphoid tissue and selective metabo-
lar dFdCTP levels and enhanced response as opposed to shorter lism of cPrPMEDAP in liver and kidney via dealkylation to the
infusions. 264 The DLT of GCB is hematologic in both humans less toxic PMEDAP metabolite, presumably leading to selective
and dogs. 245,265 toxicity in target as opposed to normal tissue. 285
Clinical Use. The role of GCB in veterinary oncology is still Clinical Pharmacology. The most common AEs observed
being defined. A preliminary study indicated efficacy when GCB with RFD are GI. Neutropenia, thrombocytopenia, elevated liver
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(800 mg/m IV over 30–60 minutes, once a week) was used in enzymes, and proteinuria are also reported. RFD can cause der-
combination with piroxicam for canine TCC 266 ; however, no matologic toxicity, characterized by otitis externa or focal pruritic,
benefit has been demonstrated for canine lymphoma, OSA, alopecic, and erythematous lesions adjacent to the pinna, on the
mammary carcinoma, or hepatocellular carcinoma. 265,267–269 Sin- dorsum, or in the inguinal areas. The underlying mechanism is
gle-agent doses have ranged from 400 to 800 mg/m IV over 30 unknown, but it has been proposed that it is secondary to drug
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to 60 minutes, once a week, but standardized dosing regimens distribution to the skin. Anecdotally, concurrent treatment with
need to be established before clinically relevant phase II efficacy antiinflammatory doses of prednisone may reduce the frequency
studies can be done. Low-dose GCB has been shown to be toler- of dermatologic changes. Although uncommon, the most severe
ated well in combination with carboplatin in dogs and cats. 270–272 and irreversible toxicity associated with RFD is idiosyncratic pul-
GCB was not well tolerated as a radiosensitizer for head and neck monary fibrosis. 285,290–294
carcinomas in dogs and cats owing to unacceptable hematologic Clinical Use. The standard dose of RFD in dogs is 1 mg/kg
and local tissue toxicity. 273 IV every 21 days as a single agent 294 or every 42 days when alter-
nated with DOX. 292 RFD has been evaluated as a single agent
5-Fluorouracil in dogs for cutaneous T-cell lymphoma, 290 multiple myeloma, 291
Basic Pharmacology. 5-Fluorouracil (5-FU) is a halogenated relapsed B-cell lymphoma, 294 and in naïve canine multicentric
analog of uracil that enters cells using a facilitated-transport system lymphoma in combination with DOX. 292 The established efficacy
shared by adenine, uracil, and hypoxanthine. 274 5-FU is converted of RFD in relapsed lymphoma makes it a reasonable choice in the
to active nucleotide forms intracellularly by a series of phosphory- salvage setting. 294 Efficacy of RFD in combination with DOX in
lase and kinase reactions to yield mono-, di-, and triphosphate the treatment of naïve lymphoma also establishes this protocol as
forms of both fluorouridine and fluorodeoxyuridine, 275,276 which an option for first-line therapy. 292 As of the time this chapter was
are incorporated into RNA and DNA interfering with synthesis written, RFD has conditional licensure by the FDA and can be
and function. 277–279 The 5-FU metabolite FdUMP is an inhibi- used only for canine lymphoma.
tor of thymidylate synthetase, leading to depletion of thymidine
5-monophosphate and thymidine 5-triphosphate. 280 The altera- Antimicrotubule Agents
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′
tions in thymidine and deoxyuridine phosphate pools caused by
thymidylate synthetase inhibition, effects on DNA synthesis and The antimicrotubule agents currently used in veterinary medicine
integrity, and effects on RNA synthesis and processing are all are structurally complex agents belonging to the taxane or vinca
thought to play a role in cytotoxicity induced by 5-FU. alkaloid class of compounds. These agents have a mechanism of