Integrated approaches to canine cancer: augmentative treatment strategies

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Integrated approaches to canine cancer: augmentative treatment strategies

Three integrative treatment modalities that, when used in conjunction with chemo and radiation, can increase the longevity and life quality of canine cancer patients.

Conventional treatments for canine cancer include surgery, chemotherapy and radiation.  In recent years, however, evidence has been mounting that additional treatment modalities can increase patient longevity and life quality. Including other modalities can also increase owner acceptance of the proposed clinical plan. This article focuses on three additional functional treatment categories — immune support; apoptosis (cancer cell suicide); and extracellular matrix therapies – that can be used alongside conventional cancer treatments.

1. Immune support

“…treatment with combination chemotherapy caused a significant and persistent decrease in B cell numbers (in dogs).” — Journal of Veterinary Internal Medicine, 2006

Compromised immunity is common in cancer patients, and a strong oncological research trend is underway to deliver immune-targeted therapies.

Cancer itself is known to be immuno-suppressive. It has been shown that dogs with cancer (lymphosarcoma and osteosarcoma) experience reductions in circulating T cells. This not only promotes the development and progression of cancer itself, but also increases the risk of infection.

Neoplasia may be immune-compromising, but it is also immune-deranging. Abnormal circulating immune complexes seem to impede effective immune responses in dogs with mammary carcinomas.

Immune support can be found in several forms:

  • One existing immune therapy for canine cancer is the plasmid DNA melanoma vaccine; several other anti-cancer vaccines in development have also shown promise.
  • COX-2 inhibitors currently used in metronomic protocols, whether pharmaceutical or botanical, reduce immuno-suppressive prostaglandins.
  • The use of immune-stimulating modified bacteria has shown to be beneficial in increasing remissions and durability of stable disease in a research setting.
  • Finally, low-dose chemotherapy and local radiation can increase immune destruction of cancers without systemic immune compromise.
  • Beta glucans are another tool the clinician can use for immune support (see below).

Beta glucans for additional immune support

Beta glucans are a group of D-glucose monomers linked by a β-glycosidic bond, found in fungal and plant cell walls. Common sources are extracts derived from various mushrooms, oats and yeast. These compounds have demonstrated strong immuno-modulatory activities based on animal and human-based research.

“β-glucans are known to exhibit direct anticancer effects and can suppress cancer proliferation through immuno-modulatory pathways.” — Investigational New Drugs, 2017

Immune-supporting beta glucans have been shown to bind to pattern recognition receptors (PARRs) on a variety of immune cells. In this way, they activate an array of immune pathways.

In humans, these compounds have been shown to increase adaptive and innate immune responses, as well as decrease cancer metastasis.  As immune-stimulating molecules, they activate macrophages, granulocytes, dendritic cells — and of particular interest in cancer immunity, natural killer cells. This leads to downstream stimulation of both T and B cells.

Beta glucans (β-1,3/1,6) extracted from yeast and administered orally to dogs elicited an immune response (and competency) similar to that of a kennel cough vaccination. Beta glucans from oat were shown to balance canine vaccination immune response by maintaining cellular immunity alongside humoral immunity. (Cellular immunity is in general the main effector branch of anti-cancer immune responses.)

It was previously assumed that oral delivery of these compounds did not yield appreciable results. However, it is now known that pinocyte microfold (M) cells, located in the small intestine, actively transport beta glucans to the Peyer’s patches.

“Glucan effects on cancer inhibition are well established.” — Anti Cancer Research, 2018

In clinical practice, the author uses both K-9 Immunity® as well as Im-Yunity® as beta glucan sources. K-9 Immunity contains a spectrum of beta glucans from a variety of medicinal fungal sources. The encapsulated formulation is preferred. Im-Yunity® contains various glucans along with a protein component, which together comprise the active ingredient, PSP.

Cases of canine hemangiosarcoma deserve special mention. At 100 mg/kg PO daily, Im-Yunity® was shown to increase median survival times to 199 days in a small cohort of dogs with splenic hemangiosarcoma. To the author’s knowledge, this is the highest median survival time reported for splenic hemangiosarcoma treatment.

Transfer factors found in low molecular weight lymphocyte extracts are thought to enhance the binding of beta glucans to immune system cells, particularly T cells, which are active in cell-mediated immunity. Transfer Factor is available commercially and the author uses it concurrently with beta glucans.

The beta glucans as a group have a high safety margin, with only rare cases of digestive upset that can be minimized by administration with food. The same can be said for Transfer Factor. However, the author avoids these immune therapies in cases of historical or active immune-mediated disease.

 2. Apoptosis: cancer cell suicide induction

“One of the few areas in the cell death field that everyone does agree upon is that having cancer cells undergo apoptosis would be a good thing.” — Carcinogenesis, 2005

Cancers uniformly lack the normal cell suicide response (apoptosis) seen in damaged, aged, infected or otherwise deranged cells. Triggering normal apoptosis in these deficient cells is a targeted approach to decreasing cancer cell burden. In fact, traditional oncologic therapies for canine cancer, such as chemotherapy and radiation, trigger apoptosis or programmed cell death of neoplastic cells.

“Owing to the fact that apoptosis causes minimal inflammation and damage to the tissue, apoptotic cell death-based therapy has been the centre of attraction for the development of anticancer drugs.” — Cell Death and Disease, 2016

However, both chemotherapy and radiation have additional effects that are not specific to neoplastic cells. The resulting toxicity leads to dose limitations.

Other compounds, called apoptogens, are capable of inducing apoptosis. An array of naturally-occurring, low-toxicity, phytochemical apoptogens selectively induce cancer cell suicide. In general, they are limited by oral bioavailability, which should be enhanced to obtain a therapeutic effect.

Common phytochemical apoptogens include curcumin, silymarin, EGCG, luteolin, lycopene, capsaicin, resveratrol and many others. Interestingly, these and other apoptogens can be extracted from dietary sources. These naturally-occurring dietary apoptogens act at multiple sites in the intracellular cascades involved in activating normal apoptosis.

“A long list of such dietary constituents is known to induce apoptosis of cancer cells without affecting normal cells.” — Biochemical Pharmacology, 2008

Additionally, several dietary apoptogens are chemo- and radio-sensitizers, enhancing the effects of chemotherapy and radiation when used concurrently. These include curcumin, silymarin and luteolin, among others.

The author uses Apocaps® as a combination source of bioavailability-enhanced dietary apoptogens. This formula may also be used alongside conventional therapies such as surgery and chemotherapy.

The author typically discontinues most therapeutic supplements, including Apocaps®, at least four days prior to surgery until ten to 14 days post-operatively. When anti-inflammatory treatments such as corticosteroids or NSAIDS are used, the author will reduce the labeled Apocaps® dose by approximately half, since Apocaps® constituents have mild to moderate COX-2 inhibiting effects.

Apocaps® has a high safety margin in clinical practice, with rare cases of digestive upset, usually loose stool. This can often be minimized by administration with food.

3. Extracellular matrix therapies

Reducing cancer spread is central to mitigating mortality and morbidity. Cancer spread occurs through a complex series of events, including mutation, loss of cancer stem cell anchoring points, migration, vascular invasion, immune dysfunction, alterations in the extracellular matrix (ECM), adhesion, and proliferation of distant tumor cells.

One possible reason for loss of remission after chemotherapy or radiation is an altered microenvironment that results from these conventional treatments. This altered matrix actually favors metastasis. In particular, the injury of cancerous tissues seems to favor conditions for regenerative responses, including aberrant neoplastic cell migration.

“Several studies demonstrated that ionizing radiation might promote migration and invasion of tumor cells” — Critical Reviews in Oncology/Hematology, 2016

“Chemotherapy by itself can instigate metastatic spread while simultaneously restraining growth of the primary tumor.” — Cancer Research, 2015

It is the author’s opinion that substantially increased attention should be placed on this subject in veterinary cancer patients.

Modified citrus pectin

The use of modified citrus pectin is one way to address this problem. Modified citrus pectin (MCP) is a complex water-soluble indigestible polysaccharide obtained from the peel and pulp of citrus fruits. To increase oral bioavailability, the citrus pectin has been modified by means of high pH and temperature treatments.

“Modified citrus pectin (MCP), a complex water-soluble indigestible polysaccharide…has emerged as one of the most promising anti-metastatic drugs.” — Carbohydrate Research, 2009

MCP has anti-adhesive properties relative to metastatic mobile cancer cell attachment. After neoplastic cell detachment and vascular invasion, endothelial attachment and neoplastic accumulation is mediated by galectin-3. MCP appears to antagonize galectin-3 adhesion. Galectin-3 also mediates mobile neoplastic cell extravasation from blood vessel to adjacent tissue extracellular matrix, where MCP appears to be active as well. Finally, MCP has the potential for increasing apoptotic responses of tumor cells to various events such as loss of anchoring, chemotherapy and radiation. Inducing normal apoptosis of cancer cells by MCP is also mediated, at least in part, by inhibiting galectin-3 anti-apoptotic function.

It has been shown in humans that high doses of MCP over one to three weeks, or modest doses long-term, increase urinary excretion of the toxic heavy metals lead, arsenic and cadmium, without increased excretion of normal dietary mineral elements.

MCP is exceptionally safe, with few to no clinical side effects. Digestive upset or allergic response is possible, but the author has not seen adverse effects clinically. The author uses approximately two to three times the human adult labeled doses pound for pound, mixed in food. Bear in mind that MCP is a pectin, so it can form a clear gelatinous substance in the presence of moisture, including dog rations.

Summary

When it comes to cancer, relative to other disease states, dog owners are often concerned about adverse survival metrics and life quality concerns. This can lead to dissatisfaction with canine cancer management, and treatment refusal. By practicing cancer care that includes immune support, cancer cell suicide induction, and extracellular matrix therapies, the clinician may experience increased opportunity for more favorable treatments.

References

Immune support

Walter CU, Biller BJ, Lana SE, Bachand AM, Dow SW. “Effects of chemotherapy on

immune responses in dogs with cancer”. J Vet Intern Med. 2006 Mar-Apr;20(2):342-7.

Rutten VP, Misdorp W, Gauthier A, Estrada M, Mialot JP, Parodi AL, Rutteman

GR, Weyer K. “Immunological aspects of mammary tumors in dogs and cats: a survey. including own studies and pertinent literature”. Vet Immunol Immunopathol. 1990. Nov;26(3):211-25. Review.

Klingemann H. “Immunotherapy for Dogs: Running Behind Humans”. Front Immunol. 2018;9:133. Published 2018 Feb 5.

Stuyven E, Verdonck F, Van Hoek I, et al. “Oral administration of beta-1,3/1,6-glucan to dogs temporally changes total and antigen-specific IgA and IgM”. Clin Vaccine Immunol. 2009;17(2):281-5.

Ferreira LG, Endrighi M, Lisenko KG, et al. “Oat beta-glucan as a dietary supplement for dogs”. PLoS One. 2018;13(7):e0201133. Published 2018 Jul 31

Bashir KMI, Choi JS. “Clinical and Physiological Perspectives of β-Glucans: The Past, Present, and Future”. Int J Mol Sci. 2017;18(9):1906.

Brown DC, Reetz J. “Single agent polysaccharopeptide delays metastases and improves survival in naturally occurring hemangiosarcoma”. Evid Based Complement Alternat Med. 2012;2012:384301.

Yoon TJ, Koppula S, Lee KH. “The effects of β-glucans on cancer metastasis”. Anticancer Agents Med Chem. 2013 Jun;13(5):699-708. Review.

Stier H, Ebbeskotte V, Gruenwald J. “Immune-modulatory effects of dietary Yeast Beta-1,3/1,6-D-glucan”. Nutr J. 2014;13:38. Published 2014 Apr 28.

Vetvicka V, Vetvickova J. “Glucans and Cancer: Comparison of Commercially Available β-glucans — Part IV”. Anticancer Res. 2018 Mar;38(3):1327-1333.

Berrón-Pérez R, et al. “Indications, usage, and dosage of the transfer factor”. Rev Alerg Mex. 2007. Jul-Aug;54(4):134-9. Review.

Apoptosis

Kaufmann SH, Earnshaw WC. “Induction of apoptosis by cancer chemotherapy”. Exp Cell Res. 2000 Apr 10;256(1):42-9. Review.

Eriksson D, Stigbrand T. “Radiation-induced cell death mechanisms”. Tumour Biol. 2010 Aug;31(4):363-72.

Baig S, Seevasant I, Mohamad J, Mukheem A, Huri HZ, Kamarul T. “Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand?” Cell Death Dis. 2016;7(1):e2058.

Khan N, Afaq F, Mukhtar H. “Apoptosis by dietary factors: the suicide solution for delaying cancer growth”. Carcinogenesis. 2007 Feb;28(2):233-9.

Khan N, Adhami VM, Mukhtar H. “Apoptosis by dietary agents for prevention and treatment of cancer”. Biochem Pharmacol. 2008;76(11):1333-9.

Limtrakul P. “Curcumin as chemosensitizer”. Adv Exp Med Biol. 2007;595:269-300. Review.

Garg AK, Buchholz TA, Aggarwal BB. “Chemosensitization and radiosensitization of tumors by plant polyphenols”. Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1630-47. Review.

Prasad NR, Muthusamy G, Shanmugam M, Ambudkar SV. “South Asian Medicinal Compounds as Modulators of Resistance to Chemotherapy and Radiotherapy”. Cancers (Basel). 2016;8(3):32. Published 2016 Mar 5.

Fantini M, Benvenuto M, Masuelli L, et al. “In vitro and in vivo antitumoral effects of combinations of polyphenols, or polyphenols and anticancer drugs: perspectives on cancer treatment”. Int J Mol Sci. 2015;16(5):9236-82. Published 2015 Apr 24.

Extracellular matrix therapies

Moncharmont C, et al. “Radiation-enhanced cell migration/invasion process: a review”. Crit Rev Oncol Hematol. 2014 Nov;92(2):133-42.

Vilalta M, Rafat M, Graves EE. “Effects of radiation on metastasis and tumor cell migration”. Cell Mol Life Sci. 2016;73(16):2999-3007.

Karagiannis GS, Condeelis JS, Oktay MH. “Chemotherapy-induced metastasis: mechanisms and translational opportunities”. Clin Exp Metastasis. 2018. Apr;35(4):269-284.

Ran S. “The Role of TLR4 in Chemotherapy-Driven Metastasis”. Cancer Res. 2015;75(12):2405-10.

Glinsky VV, Raz A. “Modified citrus pectin anti-metastatic properties: one bullet, multiple targets”. Carbohydr Res. 2009 Sep 28;344(14):1788-91.

Tehranian N, et al. “Combination effect of PectaSol and Doxorubicin on viability, cell cycle arrest and apoptosis in DU-145 and LNCaP prostate cancer cell lines”. Cell Biol Int. 2012 Jul;36(7):601-10.

Eliaz I, Hotchkiss AT, Fishman ML, Rode D. “The effect of modified citrus pectin on urinary excretion of toxic elements”. Phytother Res. 2006 Oct;20(10):859-64.

Zhao ZY, et al. “The role of modified citrus pectin as an effective chelator of lead in children hospitalized with toxic lead levels”. Altern Ther Health Med. 2008 Jul-Aug;14(4):34-8.

Editor’s noteIf you are interested in learning more about Dr. Dressler’s approach to managing canine cancer, he has created a private video training series, sponsored by Functional Nutriments, that is free to veterinarians. You can find it at FunctionalNutriments.com/IVC.

Disclosure Statement

The author of this publication developed the Apocaps® formula and is a paid consultant for Functional Nutriments, LLC. He has no equity interest in either Functional Nutriments, LLC or Apocaps®.