Page 213 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

192 PART 3 Therapeutic Modalities for the Cancer Patient

uptake of streptozotocin is dependent on the GLUT2 transporter Antitumor Antibiotics
and expression of this transporter determines sensitivity of both The antitumor antibiotics consist of natural products from micro-
167
and pancreatic beta cells.
166
insulinoma

VetBooks.ir the blood after IV administration with a reported half-life of 15 bial fermentation including the anthracyclines, mitomycins, and
Clinical Pharmacology. Streptozotocin is rapidly cleared from
actinomycins that have yielded clinically useful compounds with
to 40 minutes in humans. 168 Streptozotocin has unique activities, diverse mechanisms of action. Included in the discussion here are
including inducing diabetes in animals 169,170 and lack of signifi- the anthracycline DOX, the anthracenedione (synthetic analog)
cant bone marrow toxicity. 171,172 mitoxantrone (MTO), and actinomycin D.
Clinical Use. Streptozotocin is used to manage insulinoma.
Limited reports of efficacy have appeared in the literature, Doxorubicin
although transient normoglycemia occurred in the experience of Basic Pharmacology. The cellular pharmacology of DOX is
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the authors. 173 The drug is dosed at 500 mg/m as an IV infusion dominated by its ability to react with a number of cellular compo-
every 2 weeks with saline diuresis to avoid renal toxicity. nents and a multimodal mechanism of cellular toxicity. Its activi-
ties include DNA intercalation and inhibition of RNA and DNA
Other Alkylating Agents polymerases 192 and topoisomerase II, 193 alkylation of DNA, 194
Dacarbazine reactive oxygen species (ROS) generation, 195,196 perturbation of
2+
Basic Pharmacology. Dacarbazine (DTIC) is a prodrug that cellular Ca homeostasis, 197,198 inhibition of thioredoxin reduc-
requires metabolic activation by the hepatic cytochrome P450 sys- tase, 199 and interaction with plasma membrane components. 200
tem 174,175 to the resulting 5-aminoimidazole carboxamide and the These processes are involved in both the antitumor effects and
active methylating intermediate methyldiazonium ion. 176 Result- AEs of DOX, with their relative contributions still open to some
ing DNA methylation products are 3-methyl adenine, 7-methyl debate.
guanine, and O -methyl guanine, 177 which are presumably Clinical Pharmacology. After intravenous dosing, DOX is
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responsible for the cytotoxic activity. extensively distributed to tissues, with binding to cellular DNA 201
Clinical Pharmacology. DTIC has poor oral bioavailabil- and anionic lipids 202,203 determining the magnitude of tissue
ity and is administered intravenously. Use in cats is not recom- uptake. 204 Elimination occurs through renal and biliary elimi-
mended because of a lack of information regarding their ability to nation of parent drug and metabolism to doxorubicinol and the
convert the parent drug to the active form. DTIC is extensively 7-hydroxy aglycone. Metabolism to doxorubicinol is via side chain
metabolized in the liver and excreted in the urine. The major DLT reduction mediated by aldo-keto reductases 205 and 7-hydroxy
is GI toxicity, although occasional severe myelosuppression can aglycone by reductive cleavage of the sugar moiety both by the
be observed. liver and extrahepatic tissues. 206
Clinical Use. In dogs, DTIC is used as a single agent, or in Rapid administration of DOX can cause an anaphylactoid-
combination with DOX or CCNU, for lymphoproliferative like reaction associated with increased plasma histamine levels. 207
diseases in a relapse setting. 178–181 It also has been used in com- Routine pretreatment with diphenhydramine typically is not
bination with DOX, with or without vincristine, for hemangio- needed as long as DOX is administered over 15 to 30 minutes.
sarcoma. 182,183 As a single agent, an IV infusion dose of 800 to DOX is a vesicant and in the event of an extravasation, cold com-
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1000 mg/m every 3 weeks has been used. 178 When combined presses should be applied. Dexrazoxane (Zinecard, 10 mg per 1
with other cytotoxics, the dose must be reduced (600–800 mg/ mg DOX IV) has been shown to substantially reduce the extent of
m IV) 179,181,183 or spread out over several days (200 mg/m /d IV tissue damage and should be given IV (different vein from site of
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for 5 days). 180,182 extravasation) immediately after extravasation, and ideally again
24 and 48 hours later. 208
Procarbazine The acute DLTs associated with DOX are myelosuppression
Basic Pharmacology. Procarbazine (PCB), like DTIC, is a pro- and GI toxicity. In dogs, cardiotoxicity is well established. 209,210
drug requiring chemical or metabolic alteration for the genera- Acute cardiotoxicity manifests as transient arrhythmias associated
tion of active metabolites. 184,185 The mechanism of action of PCB with transient increases in circulating histamine and cathechol-
could involve multiple interactions, including inhibition of DNA amines and is usually of little clinical significance. Cumulative car-
and RNA synthesis, but a predominant role for DNA methylation diotoxicity manifests as a decrease in myocardial contractility and/
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to form O -methyl guanine seems likely. 186 or arrhythmias, which often leads to congestive heart failure. The
Clinical Pharmacology. PCB is rapidly and completely damage is irreversible and carries a grave prognosis. The mecha-
absorbed after oral administration followed by rapid disappearance nism of cumulative cardiotoxicity by DOX is complicated, 211 and
of the parent compound and subsequent appearance of metabo- may involve ROS generation, 212 altered calcium homeostasis, 213
lites. 187 PCB and/or metabolites equilibrate rapidly between the topoisomerase-IIβ–mediated DNA double-strand breaks, 214 or
blood and cerebrospinal fluid. 188 IV delivery has been tested in upregulation of death receptors on cardiomyocytes. 215 It is con-
humans with the appearance of neurotoxicity not seen with oral troversial whether or not every dog should have cardiac evaluation
delivery, suggesting that first-pass metabolism associated with oral with echocardiogram and electrocardiography before receiving
dosing significantly alters the spectrum of exposure to parent drug DOX, but evaluation should be considered in dogs with known
versus metabolites. 189 heart disease and breeds predisposed to dilated cardiomyopathy
Clinical Use. PCB most frequently is used in combination with (e.g., Boxer, Doberman Pinscher). Dogs with normal baseline
mechlorethamine or CCNU, vincristine, and prednisone for lym- myocardial function should be able to safely receive a cumulative
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phoma. 111–113,190,191 It is dosed at 50 mg/m /d PO for 14 days of DOX dose of 150 to 240 mg/m . For dogs with impaired systolic
a 21- or 28-day cycle. Every other day dosing or use of reformu- function or dogs in which the cumulative dose has reached this
lated capsules is required for smaller dogs and cats owing to the maximum, dexrazoxane can be administered immediately before
limitations of available capsule sizes. DOX to help prevent cardiotoxicity. 216 In cats, DOX can cause