Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 15 CANCER CHEMOTHERAPY
sion times are employed. The area under the curve
(AUC) correlates well with dose of drug administered.
The volume of distribution is much larger than total
body water, indicating protein binding. Disposition in
plasma is characterized by a biexponential elimination
model. Paclitaxel is not believed to cross the blood–
brain barrier. The major route of excretion is biliary,
with a small component of renal excretion.
Adverse effects
● Myelosuppression occurs 3–7 days following administration
but the dose-limiting toxicity in the dog
appears to be a reaction to the drug’s vehicle.
● Cremophor EL and alcohol induce mast cell degranulation,
causing hypotension, cutaneous erythema
and pruritus.
● Alopecia is significant in dogs administered
paclitaxel.
Known drug interactions
None have been reported.
ALKYLATING AGENTS
Mechanism of action
Alkylating agents react chemically with nucleic acids
(DNA) and proteins but, in general, their cytotoxicity
has been correlated most closely with their capacity to
react with DNA. In DNA, alkylating agents react with
guanine or cytosine bases, substituting alkyl radicals for
hydrogen atoms. This may cause DNA strand breaks
and, in the case of bifunctional alkylating agents (which
have two alkyl groups, each of which can bind a DNA
molecule), lead to DNA intra- or interstrand crosslinks
or DNA–protein crosslinks. This prevents normal function
of DNA (DNA replication and consequent RNA
transcription and translation) at all phases of the cell
cycle.
The agents are therefore cell cycle phase-nonspecific
and the nitrogen mustard and the nitrosoureas are
sometimes classified as nonselective, phase nonspecific.
They are lethal to resting cells, although cell division is
required for the lethal event to be expressed. Thus, this
group of drugs may be effective against slowly growing
as well as rapidly growing tumors.
Mechanisms of resistance
Numerous mechanisms of tumor cell resistance to
alkylating agents have been described in vitro. Specific
mechanisms include:
● decreased drug uptake
● increased repair of drug-induced damage
● increased drug inactivation
● increased inactivation of cytotoxic metabolites.
Drug-specific examples are listed below but knowledge
of these mechanisms has not yet proven clinically useful
to improve chemotherapy response.
Decreased drug uptake or accumulation by cancer
cells has been linked to resistance to melphalan and
mechlorethamine.
Increased repair of drug-induced damage is a mechanism
of resistance to nitrosoureas mediated by increased
cellular levels of O6-alkylguanine DNA alkyltransferase,
which repairs O6-alkylguanine DNA intermediates.
Depletion of O6-alkylguanine DNA alkyltransferase
reverses drug resistance in vitro, but attempts to do so
in vivo have so far proved too toxic for clinical use.
Increased drug inactivation resulting from alterations
in metabolism involving thiol compounds such as glutathione
has been documented for a variety of alkylating
agents such as nitrosoureas, chlorambucil and melphalan.
The clinical significance of glutathione-mediated
drug inactivation is uncertain. Recent reports suggest
that glutathione conjugation may also contribute to
efflux of chlorambucil and melphalan from the cell by
MRP. Human clinical trials designed to pharmacologically
modify glutathione synthesis or inhibit glutathione
S-transferase (which catalyzes conjugation of glutathione
to drug substrates) have not yet yielded clear
results.
Increased inactivation of cytotoxic cyclophosphamide
metabolites by high levels of aldehyde dehydrogenase in
tumor cells has been linked to resistance to cyclophosphamide.
Although inhibitors of aldehyde dehydrogenase
have been identified, their value in reversing clinical
drug resistance is unknown.
BCNU
Other names
Carmustine
Clinical applications
BCNU is primarily indicated in humans for palliation
of malignant glioma, multiple myeloma and lymphoma.
Objective tumor shrinkage was observed in a dog with
an astrocytoma. BCNU has also been combined with
vincristine and prednisone for the treatment of canine
lymphoma. Remission rate and duration of remission
(86% and 183 days) were comparable to other multiagent
protocols and neutropenia was the dose-limiting
toxicity.
Formulations and dose rates
• 50 mg/m 2 administered IV over 20 min and repeated every 6
weeks
• There is no information available for cats
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