Page 331 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 16 Supportive Care for the Cancer Patient 309

oil supplementation than dogs because of greater effects on plate- Antioxidants/Supplements
let reactivity, resulting in alterations of clotting times. 354 A safe The use of supplements, most commonly substances termed “anti-
and tolerable dose for fatty acids in dogs can be extrapolated from
VetBooks.ir studies in cardiac cachexia in dogs, 355,356 in which the dosage used oxidants,” has grown tremendously in the past 15 years. Approxi-
mately 65% of pet owners are using some sort of alternative
was 45 mg EPA and 25 mg DHA per kilogram of body weight
(e.g., 1 teaspoon per 20 kg body weight). Unpublished data from treatments; more than 30% of owners are giving their pets oral
our laboratory suggests that the same dosing schedule did not alter supplements, and more than 50% say their veterinarian approves
thromboelastography results in cats. of this use. 374 More recent epidemiologic data on conventional
During RT the paradigm may be altered, because RT has the diets and supplementation shows that more than 50% of own-
effect of causing irreparable damage to tumor cellular micro- ers incorporate some sort of nontraditional feeding pattern after
structure, resulting in apoptosis of cells and negative effects on cancer diagnosis, and 39% supplement the diet of their dog. 375
surrounding tissues. Polyunsaturated fats, the longest being the This is a concern, because most oncology referral centers generally
omega-3 fatty acid DHA, may be oxidized to a greater extent dur- recommend that clients refrain from using antioxidants or herbal
ing RT, and this may lead to increased membrane compromise and supplements, and from feeding raw and home-prepared foods
cellular death. 357 Surrounding tissues may not exhibit as aggres- because of the lack of clinical data to support their use. 376
sive of an inflammatory action because of the hastened eicosanoid It is clear that antioxidant and oxidative balance is altered in
response with EPA and other essential fatty acids quenching this tumor tissue. Canine mammary cancer tissue has an increased
proinflammatory response, which may lead to less surrounding presence of lipid peroxidation coupled with an increase in upreg-
tissue damage. 358 This principle has not been studied in veterinary ulated antioxidant mechanisms, including glutathione peroxi-
patients but has proven to diminish radiation-induced tissue dam- dase, glutathione, superoxide dismutase, and catalase. 377 In one
age in pig models. 359 study of dogs with lymphoma, reductions in serum antioxidants
(tocopherols) and increased lipid peroxidation were observed,
Vitamins and Minerals whereas total oxygen radical absorption capacity and glutathione
peroxidase were increased, suggesting an increase in antioxidant
Essential vitamin and mineral supplementation is an interesting capability. 378 Therefore the addition of an antioxidant is unlikely
area of investigation in human cancer, with nutrients such as vita- to have a dramatic effect on the overall antioxidant capability of
min A, vitamin D, and selenium receiving attention. 286,288,359–363 tumor cells compared with normal tissue.
Much of the research has centered on cancer prevention rather Further complicating this issue, many substances given as
than cancer treatment. That being said, certain vitamins and min- antioxidants may be considered pro-oxidants in some environ-
erals are being used in therapeutic clinical trials in humans because ments. 379 Many isothiocyanates, flavonoids, and carotenoids actu-
of their ability to reduce tumor cell proliferation in preclinical ally may cause alteration of cell signaling or depletion of specific
models. Vitamin A, in the form of retinoic acid and synthetic antioxidant systems. 379,380 Furthermore, the evidence increasingly
derivatives, has been used to treat certain cancers; however, dis- indicates that many of these compounds upregulate or downregu-
cordant effects on nuclear signaling occur with different heterodi- late specific cell signaling systems to alter the proliferative cycle
mers. 361–363 Some heterodimers drive the proliferative response, from activities such as cell cycle disruption (CDKs, p16, p21),
whereas others diminish cell proliferation. 364 Their use cannot be prosurvival signals (nuclear factor-κB [Nf-κB], AKT), mitochon-
recommended at this time. drial-induced apoptosis (Bcl and Bax family proteins), and prolif-
Low concentrations of vitamin D in people may promote erative signaling pathways (i.e., mitogen-activated protein [MAP]
tumorigenesis, and treatment with active vitamin D may cause kinase, tyrosine kinase [TK] activity). 381–383 Primary cancer cell
tumor regression in some cases 286–288,365 ; however, the antip- culture data in lymphoma and OSA supports these principles.
roliferative form, calcitriol, can be toxic at high levels, and the Astaxanthin and lycopene, two carotenoids, showed limited anti-
repercussions of vitamin D toxicity can lead to calcification of soft oxidant capability in canine OSA cells lines, and when coupled
tissue and hypercalcemia, resulting in low margins of safety. This with doxorubicin or irradiation, no protective effects were seen
was illustrated in a recent trial in dogs with MCTs, in which many on cell proliferation indices or cell death. 384,385 Isoflavones appear
patients developed clinical signs of hypercalcemia, inappetence, to induce mitochondrial apoptosis in canine lymphoma cells. 386
and vomiting. 365,366 Further examination of the flavonoid baicalein from Scutellaria
Selenium has generated considerable interest in certain human root, shows mitochondrial-induced apoptosis. 387 Rosemary and
neoplastic diseases, such as lung, dermal squamous cell, and pros- curcumin extracts supplemented at slightly higher than presumed
tatic carcinomas. 367–370 Low serum concentrations have been asso- physiologic doses have antineoplastic activity and act synergisti-
ciated with an increased risk of prostatic cancer in humans 367,369 ; cally in round, spindle, and epithelial canine cancer cells to pro-
however, meta-analysis of human intervention studies suggests no mote cell death; they do not hinder chemotherapeutic cell death
definitive benefits from selenium supplementation in the treat- and may augment it. 388 These in vitro data must be interpreted
ment or prevention of neoplastic diseases. 282 with caution because another recent study examining the isothio-
B-vitamins of interest include folate and vitamin B (cobala- cyanate sulforaphane, which has been touted to protect cells dur-
12
min). The interest once again derives from human literature, ing cisplatin chemotherapy, may also augment cell growth in the
which has shown that the effects of these two vitamins on epigen- canine OSA cell culture environment. 389
etic alterations may affect tumor suppressor and oncogene expres- Even if some of these compounds have little to no detrimental
sion over time. 371–373 Considering the consistent intake of folate effect on current chemotherapy or RT protocols, the limiting fac-
and cobalamin in the pet population, a considerable gap exists in tor to their effective use is absorption, hepatic metabolism, and
applying these paradigms of subclinical deficiency to pet popula- the attainment of tissue concentrations that recapitulate what
tions. Furthermore, the lack of clinical or in vitro investigation has been used in vitro. 381 Pharmacokinetic data has been col-
prevents any postulation as to their effects on cancer cells. lected on three nutraceuticals: genistein in cats (an isoflavone),