MEDICINE CHEST IN A BOTTLE?
By Susan Thorpe-Vargas Ph.D

Cancer is epidemic in dogs and pandemic in cats. It seems that our pets are particularly at risk for cancer because they interact so closely with the environment (unless of course you lick your paws after crossing the street). Other outside influences can also be responsible for the mutations and changes in cellular genetics that lead to cancer. Because we all breathe an atmosphere that contains oxygen and digest food, our bodies are constantly producing free radicals--highly reactive oxygen molecules that occur naturally in the body because of metabolic processes. Environmental factors such as air pollution, radiation, pesticides, herbicides, many drugs and exposure to cigarette smoke react within the body to cause free radical production. Dogs with squashed up noses, like pugs and certain breeds of cats are especially vulnerable to second-hand cigarette smoke. Free radicals can damage DNA, affect the structure and function of cell membranes and damage certain regions of proteins that have enzymatic functions. Older animals are more at risk due in part to increased levels of free radicals as well as an impaired ability of their immune systems to eliminate altered cells. Very inbred dogs also have weakened immune function. http://cc.ysu.edu/~helorime/inbrimmune.html

Loss of immune function

Inbreeding, referred to as line breeding by many dog and cat breeders, leads to loss of immune function. In order to function, the immune system has to be able to recognize “self” from “non-self”. The portion of the genome that codes for the genes that help us recognize “self” is called the MHC--the Major Histocompatability Complex. These genes are located very close to each other and therefore it is very rare for recombination to occur. This in effect means that the genes from each parent are inherited intact as haplotypes If the parents are closely related, then the possibility exists that they share the same genes at that site, i.e., they are homozygous by decent. In a highly inbred population, what is the likelihood that the parents share the same haplotypes? What happens to the puppies or kittens that inherit a duplicate copy of that same haplotypes? This would essentially cut the functionality of the immune response in half- not a good thing.

Spay and Neuter

Altering dogs can affect their susceptibility to cancer. In females, spaying before their first heat cycle reduces the risk of mammary tumors to 0.05%. It increases to 8% after one heat cycle and goes up to 26% after the second heat. Obviously, there must be hormonal factors contributing to this trend.

On the other hand, early spay and neuter actually increases the probability that cancer will occur in certain canine populations. One study showed that spayed females were 5 times more likely to develop hemangiosarcoma and neutered males had a 2.4 times greater risk then intact dog to develop this type of cancer. Another study, involving 3218 dogs, showed that males, neutered before one year, had a significant increase in the incidence of bone cancer. A similar study showed that this risk was twice as high for neutered dogs as it was for intact males. Although it is commonly believed that altering dogs will improve their risk of cancer current studies do not support this idea. The only exception is neutered dogs will never develop testicular cancer.

The Number One Killer?

Cancer is the number one disease related death in dogs It is believed that about 65 million pet dogs are at risk of developing cancer just in the United States and twenty-three percent of all dogs, regardless of age, and 45 percent of dogs ten years of age or older die of cancer. Man's best friend has a cancer rate comparable to humans, and shares many of the basic biological features. We differ only in the types of cancer we tend to develop. Cats are more likely to develop lymphomas, especially those who are infected with Feline Leukemia virus, and injections site sarcomas. Not surprisingly, cats infected with Feline Immunodeficiency virus are more susceptible to all types of cancers. The age of onset 15 years ago used to be between 2-5 years of age, but now it is most likely to be seen between 8-10 and occur somewhere in the GI tract. Although not as common as cats, dogs are also more frequently diagnosed with lymphomas and sarcomas, whereas humans primarily develop breast, prostate and lung cancers. Whatever their name, these cancers are always caused by a breakdown in the biological control over cellular growth that we now know results from alterations in the genes that mediate normal cell replication and cellular death.

However, before we can understand what goes wrong and why cancers occur, we need some background on the normal processes involved.

The disease with a thousand faces

Cancer is not just one disease but is the general name for more than 200 different types of malignancies. Cancers are classified by the tissue type from which they arise. To illustrate:

• osteosarcoma-bone cancer
• melanoma-skin cancer
• lymphoma-cancer of lymph nodes
• leukemia – blood cancer

Every cellular type has its own form of cancer. The one thing all cancers share in common is uncontrolled growth. Cancer occurs when cells lose control over critical checkpoints during the process of one cell splitting and becoming two cells. This control over cellular replication is in the hands of several specific types of genes.

Two classes of genes are suspected of being associated with the occurrence of cancer. A mutation in a tumor suppressor gene is like having faulty brakes in your car. Just as their name implies, tumor suppressor genes function by making sure there are no mistakes in the genes that are replicated prior to one cell becoming two. In this "quality control" process, if errors are detected, the cell is instructed not to divide. Thus, tumor suppressor genes put the brakes on cellular division. The other class of genes thought to be involved with preventing cancer is called proto-oncogenes. Researchers have found that these genes "code" for proteins involved in mechanisms that regulate the social behavior of cells. Signals from those cells in the immediate environment induce their neighbors to divide, differentiate and even undergo apoptosis. So, this type of gene is involved in promoting the normal growth and division of cells and could be likened to your car's accelerator. A change in the genetic message - a mutation, can turn the proto-oncogene into an oncogene and cause your accelerator to become stuck, thus initiating "runaway" cellular replication. Nevertheless, there seem to be no pattern to these mutations. What is so frustrating for both researchers and clinicians alike is that different combinations of mutations are found in different types of cancer and even in cancers of supposedly the same type in different patients. What is most important to remember is that cancer begins as a single abnormal cell that somehow is able to hide from the body’s defense system and begins to multiply out of control.

How do we protect our companion animals?

Multiple studies have discovered that phytonutrients found in raspberries are able to protect us from cancer and can even shrink some types of cancer tumors. These substances can also act as an antibacterial and as an antiviral agent. Does this sound too good to be true? One particular substance found in this natural “medicine chest”, is a series of compounds called ellagitannins. The highest levels are found in raspberries, but the ellagitannins are also in certain types of grapes, strawberries, blackberries, blueberries and some nuts too. In 2001, a study published by Dr. Gary Stoner at Ohio State University, showed that components in the seeds and berry, but particularly ellagitannins, inhibited the initiation and promotion/progression stages of esophageal cancer in a dog. Considering the potential benefits, this is an extremely important finding. In addition, edible berries, including raspberries also inhibit angiogenesis. This is a term used to describe the development of blood vessels needed for tumor growth.

We do not as yet know all of the functions of the ellagitannins in terms of cancer. A study at Hollings Cancer Center, Medical University of South Carolina has shown one of the ways they work is to "turn on" a normal cellular process called apoptosis. Apoptosis is "science speak" for something called programmed cell death. This natural cell death is just one of several ways the body protects itself from cancer. In aging animals, cellular replication mistakes can occur. Cancer cells somehow become immune to the signals that cause cells to self-destruct, so they become virtually immortal and reproduce indefinitely.

So, what causes most mutations?

We and our pets live in a polluted environment. For instance, the outgassing from asphalt on a hot summer day produces the deadly carcinogen benzo{a}pyrene, the same chemical found on meat that has been charcoal broiled. This is just but one example. Exposure to pesticides and other such chemicals in the environment can cause the mutations in genetic material that lead to cancer. Even normal metabolic processes like breathing and exercise produce free radicals that can wreak havoc on our cellular DNA. We can protect our animals from mutations caused by environmental toxins and free radicals by giving them antioxidants. Guess what? Ellagitannins are also very good antioxidants and chemoprotective agents. Researchers at Wayne State University have a theory about how ellagitannins might work. The liver produces enzymes that rid the body of toxins. These enzymes break down or chemically change toxic substances we ingest or inhale so that they can be excreted. During this detox process, the breakdown products, called metabolites, are frequently more damaging then the original substance. It appears that ellagitannins are able to safeguard the liver from damage caused by these breakdown products. Another theory held by some investigators is that ellagitannins are able to protect our genetic material from certain types of chemical reactions that lead to misreading of damaged DNA.

Why does chemotherapy and radiation eventually stop working?

It is becoming clear that normal therapeutic cancer treatment works by turning on apoptosis. We used to think that chemotherapy and radiation killed rapidly dividing cells, which is why these procedures were able to shrink tumors. However, at some point these treatments begin to lose their effectiveness. Why is that? Scott Lowe, a research scientist at Cold Spring Harbor Laboratory may have found the answer. Instead of killing these cells, chemotherapy and radiation damage their cellular DNA. This alerts the cellular watchdogs that control the cell cycle that something is wrong and tells the cell to stop dividing or to commit suicide. Therefore, chemotherapy and radiation act somewhat like a "vaccination" that works by helping the body help itself. The evidence for Dr. Lowe's theory is pretty convincing, because when these treatments start to fail, researchers have found that the genes that control apoptosis are no longer functioning.

Why don't ellagitannins induce normal cells to commit suicide?

As we know, cancer cells become immortal; this means that they are able to replicate themselves after something called the Hayflick limit has been reached. The Hayflick limit is the number of "allowed" cellular replications. Each cell type has its own limit. Human cancer studies show that mutations in the tumor suppressor gene called p53 account for many of the tumors found. One of the functions of this gene is that it normally prevents cells with damaged DNA from proceeding through the cell cycle. The presence of the protein product encoded by p53 turns on the waf-1 gene. The waf-1 gene produces a protein that normally inhibits the activity of several similar cellular proteins called kinases. These proteins are involved in stopping cell cycle progression. A mutation in either the p53 or waf-1 gene can cause the loss of that "emergency brake" function and allow uncontrolled growth. However, only "damaged" cells are induced to commit suicide and so normal cells are not affected.

Other Phytochemicals found in raspberries.

Besides ellagitannins, the short list of other beneficial compounds found in red raspberries includes anthocyanins, salicylic acid, quercitin and catechins. Some recent work has shown that these anthocyanins are more effective then Vitamin E and equivalent to ibuprofen and naproxen in inhibiting the COX-1 and COX-2 enzymes. Both Cox-1 and Cox-2 are associated with the pain of arthritis and other inflammatory diseases, and Cox-2 inhibition is positively linked to preventing breast cancer. Funding for this specific research in dogs has been supported by the AKC Health Foundation and several breed clubs.

Other than their anticancer properties, anthocyanins provide many other health benefits. Among these are controlling diabetes, improving circulation and aiding the retention of motor skills and preventing the loss of memory due to aging. Dogs do become senile. In canines it is called canine cognitive dysfunction, aka as “doggie Alzheimer’s” Salicylic acid may have the same effects as aspirin in protecting us from cancer and the progression of atherosclerosis. Both quercitin and catechins are flavonals that are known to have antioxidant benefits including cancer prevention, and quercitin may act as an antihistamine also. Besides the anticancer properties of ellagitannins they can protect us against infections.


An Antibacterial and an Antiviral agent

Ellagitannins can act as antibacterial agents and as antiviral agents too, and now we know how. Think of the genetic material of bacteria as a rubber band that is all twisted up. In order to replicate, the DNA must untwist itself through a process requiring the enzyme gyrase. Ellagitannins inhibits gyrase activity so replication of the bacterial DNA is restricted. More importantly, bacteria cannot easily become resistant to this type of antibacterial action. Resistance to antibiotics has become a real concern to the international medical and veterinary community. A federal government task force noted that antibiotic resistance was “a growing menace to everyone” but both young and old animals, and those with weakened immune systems are especially at risk.

Besides its antibacterial action, ellagitannins have antiviral activity also. Viruses do not have the ability to replicate themselves. Instead they must "hijack" the host cell and insert their own DNA into the host cell genome. This requires several enzymes and ellagitannins inhibit these enzymes also. It especially helpful with the retroviruses, like FIV (Feline Immunodeficiency virus) as well as feline leukemia virus (FeLV), as it specifically inhibits reverse transcriptase.

Diabetes and the Protective effects of ellagic acid.

Our companion animals also suffer from diabetes, especially cats, and in dogs the Samoyed breed is extremely susceptible. Diabetes m. is wide-spread in cats because they are eating a grain based diet and, as obligate carnivores, they should be eating meat instead. The disease is common in the Samoyed because they are genetically predisposed to Type I Diabetes mellitus. New data shows that ellagic acid is very effective in preventing damage to the eyes, kidneys, heart and the small capillaries of the feet that occur with high glucose levels. It does this by inhibiting an enzyme called aldose reductase. This enzyme is responsible for the production of protein-sugar products called AGE (Avanced Glycation End-Products). These end products cause the damage of small blood vessels that leads to the blindness, kidney damage, stroke and heart attacks and loss of limbs associated with both forms of diabetes. In addition, ellagic acid, as well as several other constituents in raspberry seed powder, enhance insulin action, decrease insulin resistance and lower blood sugar, and have multiple anti-inflammatory effects and decrease oxidative stress as well as lower blood pressure.

Just like in human medicine many people are turning to alternative forms of veterinary treatment and prevention. We also share a similar biology and live in the same environment, so research and treatment for many chronic illnesses, as well as cancer, can benefit our companion animals as well as ourselves. Thus, the positive effect of raspberry ellagitannins upon their life expectancy and the enumerable protective effects of ellagic acid correlate directly to the health of our beloved pets.

Dr. Susan Thorpe-Vargas shares her life with two Samoyed dogs, Max and Chloe, and rescue Siamese kitty, Sidney. Scientific citations that support this article can be found at SMDI.org