Cancer Treatment: The Critical Factors-2

Step Three: Protecting Against AnemIA

How To Implement Step Three
Anemia diminishes the chances that a cancer patient will survive. Since red blood cells carry oxygen, fewer numbers of red blood cells result in less oxygen transport. When normal cells are oxygen deprived, they lack the vigor to overcome cancer. Cancer cells, on the other hand, thrive in a low oxygen environment. The journal Cancer reported that anemia increased the risk of mortality in cancer patients by about 65% (Caro et al. 2001).

Anemia is defined functionally as lack of sufficient red blood cells to maintain tissue oxygenation. Anemia develops when the demand for new red blood cells exceeds the capacity of the bone marrow to produce them. This may be due to inadequate red blood cell production, as occurs when cancer or cancer therapies inhibit the production of erythropoietin, a glycoprotein hormone secreted by the kidney, which acts on stem cells of the bone marrow to stimulate red blood cell production (Spivak 1994).

Cancer-related anemia also results from activation of the immune and inflammatory systems (responses orchestrated by the tumor), leading to an increased release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1). Such cytokines circumvent the ability of the bone marrow to respond to available circulating erythropoietin, resulting in lesser numbers of oxygen-carrying red blood cells being produced (Cazzola 2000). In addition, the lifespan of red blood cells (normally 120 days in men and about 110 days in women) is shortened in cancer-related anemia; thus, production cannot compensate sufficiently for the shorter survival time. The energy-depleting cycle of abnormal metabolism (leading to malnutrition and wasting disease) also is a contributing factor to the progression of anemia.

Weakness, fatigue or faintness, shortness of breath and increased heart rate, headaches, confusion, dementia, depression, cold extremities, dizziness, pallor, and sore mouth are complaints of anemia that complicate recovery. Severe anemia may also result in heart failure.

Too many oncologists wait for anemia to develop before prescribing drugs like Procrit® and Aranesp® to boost red blood cell production. Other oncologists have prescribed high doses of drugs like Procrit® in an attempt to push levels of hemoglobin (the protein in blood that binds with oxygen) to the upper end of the normal reference range. This was done based on research indicating benefits to cancer patients with higher hemoglobin measurements.

Based on new research findings, the FDA is mandating a black box warning on drugs like Procrit®, AranespI® and Epogen® that warns oncologists to not over-dose these drugs for the purpose of pushing hemoglobin up beyond 12 g/dL (grams per deciliter of blood). The reason for this new black box warning are increased risks of death reported in certain cancer patients who were prescribed higher doses of these red blood cell stimulating drugs.

Based on the conflicting findings that exist today, cancer patients should continue to aggressively protect against anemia, but should not take higher-than-recommended doses of Procrit and other red blood cell boosting drugs.

One problem that cancer patients encounter is that some insurance companies will not pay for expensive drugs like Procrit unless severe anemia is demonstrated. Patients should advocate for immediate access to these red blood cell boosting drugs if indications of anemia manifest, such as low hemoglobin. Anemia appears to contribute to angiogenesis--the vascular network supplying life to the tumor. Vascular endothelial growth factor (VEGF) is an endothelial cell specific mitogen, an agent that induces cell division. The expression of VEGF appears to be an indicator of the angiogenic potential and correlates with the biological aggressiveness of a tumor.


How to implement step THREE

If your hemoglobin or hematocrit levels indicate you are anemic or that you are not in optimal ranges, ask your physician to prescribe an individualized dose of Procrit.
In order for Procrit to effectively boost red blood cell production, it is essential that your body have adequate iron stores. Even if you have adequate iron stores prior to Procrit therapy, the rapid production of red blood cells induced by Procrit may eventually deplete total body iron stores. Therefore, it is important to obtain baseline studies to exclude the presence of iron deficiency.
Note: Iron deficiency is best diagnosed by checking the serum ferritin to see if the values are low. Many physicians obtain a serum iron and serum iron binding capacity and divide the former by the latter to obtain the transferrin saturation. If this result is < 10%, there is a probability of iron deficiency anemia (IDA). A more modern approach to a diagnosis of iron deficiency anemia, however, is to check the serum ferritin; if it is greater than 220, IDA is essentially ruled out. However, if the serum ferritin level is lower than 220, a blood test called the soluble transferrin receptor (sTfR) assay should be obtained. This measures the receptors for transferrin--receptors that bind to the available iron. If this value is 28 or higher, there is a significant chance of IDA. Regular blood tests to assess ferritin and, when indicated, sTfR will assist your doctor in determining whether or not you need iron supplementation.
Dietary supplements that can help protect against anemia include folic acid (800 mcg/day), vitamin B12 (500 mcg/day), and melatonin (3-10 mg/day, taken at night) (Vaziri et al. 1996; Herrera et al. 2001).

Step Four: Inhibiting the Cyclooxygenase-2 (COX-2) ENZYME

How To Implement Step Four
Our diet, the amount of saturated and polyunsaturated fat we eat, and the unfavorable fats that we create in our bodies play a crucial role in the development and progression of malignancy. A critical pathway that represents a "Rosetta Stone" to all aspects of our health is that involving the metabolism of omega-6 fatty acids leading to either di-homo gamma-linolenic acid (DGLA) or to arachidonic acid.

These "roads" are called the eicosanoid pathways. The metabolism of DGLA leads to the production of fats that are actually beneficial to our health, that is, good eicosanoids. Unfortunately, in today's world, this is the "road less traveled" for most people. The metabolism of arachidonic acid, the bad eicosanoid pathway, leads to most of the health maladies currently faced by our society. A key enzyme in the bad eicosanoid pathway is cyclooxygenase (cyclooxygenase or COX). It is the COX-2 enzyme that results in the production of prostaglandin E2 or PGE2.

Initially, scientists believed COX-2 was merely an inducible response to inflammation. It is now speculated that COX-2 performs biological functions in the body, particularly in the brain and kidneys as well as the immune system. COX-2 becomes troublesome when up - regulated (sometimes 10- to 80-fold) by pro - inflammatory stimuli (interleukin-1, growth factors, tumor necrosis factor, and endotoxin). When over - expressed, COX-2 participates in various pathways that could promote cancer, that is, angiogenesis, cell proliferation, and the production of inflammatory prostaglandins (Sears 1995; Newmark et al. 2000).

A number of researchers have established the COX-2 cancer connection:

The Wall Street Journal (September 7, 1999) reported the results of a trial involving a group of rats given a potent carcinogen along with a COX-2 inhibitor. Rats treated with the COX-2 inhibitor experienced a 90% reduction in cancer compared to a group of rats not given a COX-2 inhibitor. Also, the tumors that appeared were 80% smaller and less numerous than in the control group.
An article in the journal Cancer Research showed that COX-2 levels in pancreatic cancer cells are 60 times greater than in adjacent normal tissue (Tucker et al. 1999).
Solid tumors contain oxygen-deficient or hypoxic areas, that is, a reduction of oxygen supply to a tissue below physiological levels. Cells low in oxygen cloud prognosis, promoting up - regulation of COX-2 and angiogenesis, as well as establishing a resistance to ionizing radiation (Gately 2000).
Greater microvessel density was observed in cancers over - expressing COX-2, compared to those with less COX-2 activity (Uefuji et al. 2000).
Within the nonsteroidal anti-inflammatory drug (NSAIDs) class (NSAIDs) is a subclass referred to as COX-2 inhibitors (cyclooxygenase inhibitors). COX-2 inhibitors are popularly prescribed to relieve pain but now have found a place in oncology. It began when scientists recognized that people who regularly take NSAIDs lowered their risk of colon cancer by as much as 50% (Reddy et al. 2000).

COX-2 inhibitors also significantly reduced colon polyps (considered precursors to cancer) in individuals with a propensity to polyp formation. Laboratory animals showed a similar benefit, that is, about 52% fewer polyps among mice treated with COX-2 inhibitors (Nakatsugi et al. 1997; Moran 2002). JAMA reported that a 9.4-year epidemiological study showed that COX-2 upregulation was related to more advanced tumor stage, tumor size, and lymph node metastasis as well as diminished survival rates among colorectal cancer patients (Sheehan et al. 1999). With more regular use of aspirin (a COX-2 inhibitor), the risk of dying from the disease decreased (Brody 1991; Knorr 2000). The journal Gastroenterology reported additional encouragement, showing that three different colon cell lines underwent apoptosis (cell death) when deprived of COX-2; when lovastatin was added to the COX-2 inhibitor, the kill rate increased another fivefold (Agarwal et al. 1999). The benefits, however, observed with COX-2 inhibitors extend beyond colon protection (Tsujii et al. 1998).

The COX-2 enzyme is increased in neoplastic epithelium in a number of other types of cancers (breast, bladder, lung, prostate, and head and neck cancers) as well as the blood vessel network surrounding the cancerous mass. Tumors expressing COX-2 are considered more treacherous than tumors that lack COX-2 (in part) because of the angiogenic (blood vessel-promoting) nature of cyclooxygenase. It appears cancer cells use COX-2 as a biological mechanism to fuel rapid cell division, growing larger tumor cells than those that lack COX-2 stimulation (Tsujii et al. 1998).

The Life Extension Foundation predicts that COX-2 inhibitors will eventually be approved to treat cancer. Progressive oncologists already have COX-2 inhibitors in their anticancer protocols, but the numbers are few. Unfortunately, the risks associated with traditional NSAIDs include gastrointestinal perforation, ulceration and bleeding and less frequently, renal and liver disease.

Blood tests to assess liver and kidney function are essential, along with serum tumor markers and imagery testing to determine gains or losses during COX-2 inhibiting therapy.

While there are potential side effects to COX-2 inhibiting drugs, some cancer patients accept this small risk in exchange for the anticancer benefit. Since the COX-2 enzyme appears an excellent target for pharmacological intervention, a number of natural COX-2 inhibitors, safe and with diverse anticancer properties, are detailed in the protocol entitled Cancer Adjuvant Therapy .


How to implement step FOUR

Ask your physician to prescribe one of the following COX-2 inhibiting drugs:

a)Lodine XL, 1000 mg once daily, or

b)Celebrex, 100-200 mg every 12 hours

Step Five: Suppressing ras Oncogene ExpressiON

How To Implement Step Five
The family of proteins known as Ras plays a central role in the regulation of cell growth. It fulfills this fundamental role by integrating the regulatory signals that govern the cell cycle and proliferation.

Defects in the Ras-Raf pathway can result in cancerous growth. Mutant Ras genes were among the first oncogenes identified for their ability to transform cells to a cancerous phenotype, that is, a cell observably altered because of distorted gene expression. Mutations in one of three genes (H, N, or K-Ras) encoding Ras proteins are associated with upregulated cell proliferation and are found in an estimated 30-40% of all human cancers. The highest incidences of Ras mutations are found in cancers of the pancreas (80%), colon (50%), thyroid (50%), lung (40%), liver (30%), melanoma (30%), and myeloid leukemia (30%) ( Duursma et al. 2003; Minamoto et al. 2000 ; Vachtenheim 1997; Bartram 1988 ; Bos 1989; Minamoto et al. 2000 ).

According to information in Scientific American , the differences between oncogenes and normal genes are slight. The mutant protein that an oncogene ultimately creates may differ from the healthy version by only a single amino acid, but this subtle variation can radically alter the protein's functionality.

The Ras-Raf pathway is used by human cells to transmit signals from the cell surface to the nucleus. Such signals direct cells to divide, differentiate, or even undergo programmed cell death (apoptosis).

A Ras protein gene usually behaves as a relay switch within the signal pathway that tells the cell to divide. In response to stimuli transmitted to the cell from outside, cell-signaling pathways are activated; in the absence of stimulus, the Ras protein remains in the "off” position. A mutated Ras protein gene behaves like a switch stuck on the "on" position, continuously misinforming the cell, instructing it to divide when the cycle should be turned off (Gibbs et al. 1996; Oliff et al. 1996). Researchers have known for some time that injecting anti-Ras antibodies, specific for amino acid 12, cause a reversal of excessive proliferation and a transient alteration of the mutated cell to one of a normal phenotype (Feramisco et al. 1985).

To establish new methods for diagnosing pancreatic cancer, K-Ras mutations were examined in the pancreatic juice of pancreatic cancer patients. Pancreatic juice was positive for K-Ras in 87.8% (36/41) of patients. When combined with p53 mutations in the stool and CA 19-9 (a blood marker for pancreatic cancer), it may be possible to identify the disease in its earliest stage. Thus, a program can be implemented that includes addressing mutant K-Ras and p53 to achieve a more favorable outcome (Lu et al. 2001).

Greater understanding regarding the activity of mutant Ras genes opens exciting avenues of treatment. Researchers found that newly formed r R as molecules are functionally immature. Precursor Ras genes must undergo several biochemical modifications to become mature, active versions. After such maturation, the Ras proteins attach to the inner surface of the cells outer membrane where they can interact with other cellular proteins and stimulate cell growth.

The events resulting in mature Ras genes take place in three steps, the most critical being the first, referred to as the farnesylation step. A specific enzyme, farnesyl-protein transferase (FPTase), speeds up the reaction. One strategy for blocking Ras protein activity has been to inhibit FPTase. Inhibitors of this enzyme block the maturation of Ras protein and reverse the cancerous transformation induced by mutant Ras genes (Oliff et al. 1996).

A number of natural substances impact the activity of Ras oncogenes. For example, a historic body of literature indicates individuals consuming large quantities of citrus products have a lower incidence of cancer. One of the essential oils within citrus products is limonene, a monoterpene that has been shown to act as a farnesyl transferase inhibitor. Administering high doses of limonene to cancer-bearing animals blocks the farnesylation of Ras, thus inhibiting cell replication (Bland 2001; Asamoto et al. 2002). A study conducted at Mercy Hospital of Pittsburgh also showed that diallyl disulfide, a naturally occurring organosulfide from garlic, inhibits p21 H-Ras oncogenes, displaying a significant restraining effect on tumor growth (Singh et al. 2000).