Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 15 CANCER CHEMOTHERAPY
Adverse effects
● The dose-limiting toxicity of carboplatin is myelosuppression,
occurring at different times in cats and
dogs. In dogs, at a dose rate of 300 mg/m 2 , neutropenia
and thrombocytopenia occur with a nadir of
14 d. At this dose rate, the probability of a neutrophil
count below 2 × 10 9 cells/L or a platelet count
of less than 800 × 10 9 cells/L is approximately 10%
or 20% for the first and second doses respectively.
In normal cats, the neutrophil nadir occurs at
approximately 17 d after doses between 150 and
210 mg/m 2 with neutropenia lasting from day 14 to
day 25 post carboplatin administration. The platelet
nadir may occur sooner at day 14. In tumor-bearing
cats, the amount of carboplatin administered based
on body surface area does not correlate with the
severity of hematopoietic suppression. Area under
the curve does correlate with severity of neutropenia
and depends in part on glomerular filtration rate.
● Anorexia and emesis may occur for several days after
treatment in dogs and cats, but are generally mild.
● Nephrotoxicity is generally not of veterinary clinical
significance but has been reported in humans. Carboplatin
may exacerbate pre-existing nephropathy
and patients with renal dysfunction should be treated
cautiously. No formula for dose reduction in the
dog or cat has been developed but in humans the
dose is decreased proportionately to the creatinine
clearance.
● Hepatotoxicity is reported in about 15% of humans
treated with carboplatin; neuropathies and ototoxicity
are reported far less commonly than with
cisplatin.
● Vascular access to previous carboplatin administration
sites, especially where the drug was given as
slow bolus IV injection, can be difficult, possibly
because of thrombophlebitis caused by the previous
drug dose. This may be avoided by diluting the drug
prior to administration.
● Carboplatin is a mild irritant if extravasated.
Known drug interactions
● As with other cytotoxics, the myelosuppressive
effects of carboplatin may be enhanced by other
myelosuppressive drugs.
● The risk of developing ototoxicity or neurotoxicity
is increased in humans previously treated with
cisplatin.
● The immune response to vaccination may be modified
if vaccines are administered to patients undergoing
carboplatin therapy.
Contraindications and precautions
Aluminum can form a black precipitate with the platinum
from carboplatin; hence the solution should not be
administered through equipment made of aluminum.
Solutions containing black precipitate should be
discarded.
ANTIMETABOLITES
Antimetabolites are successful anticancer drugs because
they interfere with DNA synthesis by competing with
normal nucleotide for incorporation into the DNA molecule
or inhibit enzymes responsible for synthesis of
nucleotides. By definition, all antimetabolites exhibit
their antineoplastic effect in the S phase of the cell cycle
and are cell cycle phase-specific drugs. Duration of
exposure of cancer cells to antimetabolites determines
their toxicity.
Cytosine arabinoside
Other names
ARA-C, cytarabine, NSC-63878
Clinical applications
Cytosine arabinoside is used in veterinary practice as a
component of multi-agent protocols for treatment of
leukemia, either lymphoid or nonlymphoid, and lymphoma.
Because it crosses the blood–brain barrier, cytosine
arabinoside is useful for treatment and prevention
of central nervous system lymphoma. It has been incorporated
into some renal lymphoma protocols.
Mechanism of action
Cytosine arabinoside is a pyrimidine nucleoside antimetabolite.
Intracellularly it is converted into cytarabine
triphosphate, which competes with deoxycytidine triphosphate
and inhibits DNA polymerase with resulting
inhibition of DNA synthesis. It is a cell cycle-specific
agent acting in the S phase.
Mechanism of drug resistance
The most frequent cellular abnormality leading to resistance
is decreased activity of deoxycytidine kinase, the
activation enzyme of cytosine arabinoside. Increased
cytidine deaminase, the cytosine arabinoside degradation
enzyme, decreased nucleoside transport sites and
decreased intracellular deoxycytidine triphosphate pools
have also been identified in resistant tumor cells. Normal
dogs have low tissue levels of cytidine deaminase.
Pharmacokinetics
In the dog, cytosine arabinoside can be administered
intravenously, intramuscularly or subcutaneously with
no differences in pharmacological disposition. The
358