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Other activities that disclose the modus operandi of the cancer cells include the recruitment of raw materials from native resources to use as part of their weaponry. This includes the utilization of iron to initiate and further tumor cell growth. It is known that ferric iron (Fe+++) is reduced by a vital cell guardian--superoxide dismutase (SOD)--to ferrous iron (Fe++). In the process of this reaction, a hydroxyl free radical [OH-] is produced that causes DNA damage by DNA strand breaks, crosslinking, and point mutations.231 These mutations are often clustered at apparent hot spots, many of which are similar to sites seen using iron to generate oxygen radicals.

These results suggest that human cells are able to produce oxygen radicals in response to tumor promoters and that this might play a significant role in the generation of tumors.231 There are many publications on the decline of SOD with age. There is also much written about the association of malignancy and other degenerative processes with SOD deficiency states.232 What appears critically important in this and all discussions throughout this volume is the balance of free radicals and free radical scavengers and the defense measures to combat the imbalance resulting in oxidative stress. In fact, in established malignancies, we are using chemotherapies and other approaches that employ the generation of free radicals to kill the very cancer cells that may have arisen from an imbalance of reactive oxygen species (ROS). As stated earlier, biology is a two-edged sword. All of biology relates to balance and communication.

Table 14 lists characteristics of societal terrorism and compares these with cellular terrorism. Possible antidotes for the latter are suggested. Perhaps in solving one problem, we solve multiple problems.

Table 14. Characteristics Common to Social and Cellular Terrorism

This table is intended to show the parallels between events that occur on a cellular level and on a societal level. Possible solutions to the cellular crises faced in prostate cancer are shown in the third column. Perhaps they will stimulate more thoughts on how we should be dealing with terrorism, which affects all humankind.

Characteristics Common to Societal Terrorism

Characteristics Common to Biological (Cell) Terrorism

Solutions, Strategies, and Considerations

Unhealthy parenting; inadequate disciplinary measures during childhood and adolescence

Damage to p53, GST, and other guardians of the genome and cell cycle; demethylation and/or hypermethylation of DNA leading to DNA adducts, cross-linking, and/or point mutations

Genetic manipulations introducing native p53; use of ONYX-15 oncolytic virus that kills cells lacking native p53; glutathione supplements

Resistance to discipline, high rate of repeat offenses (recidivism)

Increased resistance to apoptosis; increase in bcl-2, bcl XL

Use of antisense oligonucleotides against bcl-2 and other antiapoptotic agents; use of Taxane chemotherapies that cause phosphorylation of bcl-2

Creation of internal instability

DNA mutation; generation of arachidonic metabolites

Minimize genetic hits by reducing carcinogens in external and internal environments, e.g., excessive alcohol, cigarettes, automobile and airplane exhaust; dietary measures to prevent demethylation or hypermethylation, e.g., use of folate, B12, methionine

Incitement of population via inflammatory rhetoric

Production of pro-inflammatory chemicals, e.g., bad eicosanoids

Dietary lifestyle changes to avoid AA metabolite excesses; reduction of meat and egg yolk rich in AA; use of refined fish oil rich in EPA (Sears approach)

Hyper-reactive to demands of society

Generation of excessive ROS

Decrease environmental exposure to ROS (UV light, ozone); stress avoidance; exercise in moderation; use free radical scavengers, e.g., selenium, vitamin E, SOD, DMSO, melatonin, fermented papaya, etc.

Illegal border crossings

Damage to cell membranes via lipid peroxidation (LPO)

Dietary changes to avoid AA metabolite excesses; use of CoQ10 to protect lipid membranes

Destruction and corruption of surveillance operations

Disruption of ISP; Ras gene activation that down-regulates PKR signal transduction pathway

Oncolytic viruses, e.g., VSV and NVD to destroy tumor cells that have defects in the ISP; Reolysin (oncolytic virus) that destroys tumors with Ras gene activation

Illegal appropriation of natural resources to create weapons of destruction

Utilization of bone-derived growth factors, e.g., TGF-b1, IGF-1, and IL-1, to promote tumor growth; use of iron to create OH radicals which damage DNA and lead to mutations

Stabilize bone microenvironment with bisphosphonates plus bone supplements and moderate resistive exercise; avoid dietary excess of iron; avoid blood transfusions (if possible); possible use of antimalarial compounds that kill tumor cells at iron-bearing sites

Ability to thrive in a low level environment and resist elimination

Tumor growth in areas of tissue hypoxia (low levels of oxygen); radiation resistance of center of tumors where hypoxia exists

Diagnose tumors before they are bulky; cytoreduce tumors with androgen deprivation prior to RT; use of surgical debulking; use of hypoxic cell sensitizers with RT, e.g., 5-FU, cisplatin low dose infusion

Recruitment of new terrorists as old ones die out

Increase in angiogenesis in areas of tissue hypoxia

Antiangiogenesis strategies such as doxycycline, androgen deprivation, reduction of PGE2 via Zone approach; anti-VEGF monoclonal antibody therapy

Difficulty in eradication in general

Increase in telomerase

Use of telomerase inhibitors, e.g., use of histone deacetylase inhibitors, nerve growth factor,233 and telomerase ASO

Difficulty in eradication of established terrorist cells

Low response rates to therapy in late diagnosed PC; higher probability of mutated disease in late diagnosed PC

Screening with earlier diagnosis; debulking of tumor surgically and with ADT

Spread of malignant credo to other parts of population

Invasion and metastasis

Antisense oligonucleotides (ASO) to uPA; early diagnosis and treatment; stabilize bone microenvironment

Suicide missions are common practice

Death of tumor cell population with death of host (patient)

Preventive medicine that invokes many of above approaches; learning early warning signals of cancer, routine use of effective screening, recognizing importance of trends and use of profiles in cancer behavior

8. Anti-Angiogenesis Treatments, Dietary Changes

Much of this has already been discussed in previous pages. The survival of the tumor cell population requires that the nutritional needs of the tumor cell be met. This may relate to the supply lines to the tumor--the vascular pathways that carry oxygen and amino acids, sugars, and fats required by the tumor for growth and function--or to the supplies themselves. Vascular pathways or blood vessels specifically arise through the process of angiogenesis, or new blood vessel growth. The major stimulant for that growth is hypoxia, or low levels of oxygen in the tissue. Hypoxia, which stimulates new blood vessel growth is also identified as a major factor relating to failure of radiation and chemotherapy protocols.

Tumor hypoxia has been shown to be an independent prognostic indicator of poor outcome in prostate, head and neck, and cervical cancers. Recent laboratory and clinical data have shown that hypoxia is also associated with a more malignant phenotype (observable physical or biochemical characteristics of an organism) as well as increased instability of the genome, resistance to apoptosis, increased angiogenesis and a greater propensity to metastasis.234 In a study of the effect of hypoxia on radiation dose needed for tumor cell killing, the dose of radiation had to be increased by a factor of 2.6-2.8 if the tumor cell population contained an average of 20% hypoxic cells.235

Because tissue hypoxia or lower partial pressures of oxygen are found more frequently in tumor cells compared to normal cells,236 consideration of therapies to reduce hypoxia and to reduce angiogenesis are reasonable strategies for clinical trials. The use of a Zone approach to calorie input (eating), according to the writings of Sears, has the potential to profoundly affect angiogenesis. This is because PGE2, a major metabolite of AA, is known to stimulate VEGF and hence angiogenesis.42,237 A carbohydrate-restricted diet focused on preventing hyperinsulinemia and the use of highly refined fish oil supplementation containing EPA to shift the pathway from AA to favorable eicosanoids has been mentioned previously, but must be strongly reinforced as a simple, inexpensive foundation to lowering VEGF levels. This certainly should be studied in a clinical trial.

In a study by Fosslien et al., the induction of the COX-2 enzyme was associated with an increase in TGF-b1 and VEGF. Of interest is that these three agents favoring the growth of the cancer cells were co-localized.237

Measures to reduce angiogenesis could involve not only reduction in PGE2 production, but also the use of antiangiogenesis agents such as ADT, which decreases androgen levels and reduces VEGF.218 Other therapies to reduce angiogenesis are shown in Table 15.

Docetaxel and Management of Androgen-Independent Prostate Cancer

Androgen hormones are produced in the adrenal glands and testis. These hormones facilitate the growth of prostate cancer cells (testosterone in particular). Hormone therapy targeted at lowering testosterone levels can be an option when prostate cancer spreads beyond the prostate gland to other parts of the body, or if it comes back after being treated before, or if it is advanced and surgery and radiation are not good treatment options for a patient. Effective hormone therapy lowers PSA levels an indicator of the amount of cancer in a patient’s body.

Although hormone therapy (ADT) can lower androgen levels, it does not cure prostate cancer. It is a management strategy which can shrink the cancer or cause it to grow more slowly. Over time, prostate cancer can become androgen independent. Androgen-independent prostate cancer (AIPC; also hormone-refractory prostate cancer) does not require androgen hormones to grow. If prostate cancer becomes androgen-independent or hormone-refractory, effective treatment options are very limited, leaving the patient with an extremely poor expected outcome (ACS 2001). However, use of docetaxel, a chemotherapy drug, has shown promise in AIPC patients (Khan et al. 2003).

Docetaxel (Taxotere®) is a drug from the taxane family of medicines that is used in chemotherapy for some types of advanced cancers. It is synthesized from an extract of European yew needles (Taxus baccata) (Beer et al. 2003b). Taxotere was approved by the FDA on June 22, 1998 for locally advanced or metastatic breast cancer that had progressed during anthracycline-based treatment or had relapsed during anthracycline-based adjuvant therapy. On December 23, 1999, Taxotere® received FDA approval for locally advanced or metastatic non-small cell lung cancer after prior platinum-based chemotherapy failed.

Docetaxel has shown promising results in the management of AIPC (Beer et al. 2003a,b; Khan et al. 2003). Used as a single agent, docetaxel had an overall PSA response rate (reduction) of 42% in four Phase II studies (Beer et al. 2003b). Even more impressive were the results of docetaxel in combination with other chemotherapy drugs (Beer et al. 2003a; Khan et al. 2003). A review of clinical trials investigating docetaxel used alone or in combination with other agents found that when docetaxel was combined with other agents, it consistently demonstrated a palliative response.

The docetaxel-based regimens were moderately well tolerated and PSA decreased by 50% or more in over 60% of patients, indicating a decrease in measurable disease and suggesting improved survival (Khan et al. 2003). Close patient monitoring is required because Taxotere® can cause allergic reactions, decreased red and white blood cells, and liver damage. Studies are ongoing to determine if docetaxel-based therapy will have a beneficial impact on overall survival rates (Hitt 2003; Smith 2003; Susman 2000).

Table 15. Tactics to Reduce Angiogenesis

Although the various tactics to reduce angiogenesis shown in this table are based on the peer-reviewed literature, only one treatment is commonly being used to reduce angiogenesis--Androgen Deprivation Therapy, or ADT.

Antiangiogenesis Tactics

Mechanism(s)

References

Reduction in VEGF

Reduction in PGE2 via COX-2; inhibition by dietary measures

Reduction in COX-2 with inhibitors such as Celebrex

39, 42, 44, 237, 238

Reduction in VEGF

Reduction in testosterone via ADT

Reduction in caloric intake (possibly)

Use of vitamin E (possibly)

218, 239, 240, 31, 63

Decrease in microvessel density (MVD)

Apoptosis of the endothelial cells using Hytrin

24

Decrease in tumor-associated macrophage (TAM) activity

Reduction in TNF-alpha, e.g., Linomide, pentoxifyllene (Trental), thalidomide, and genistein, leads to decreased VEFG

242, 243

Increased production of GM-CSF

GM-CSF increases production of plasminogen activator inhibitor Type 2 (PAI-2), e.g., Linomide

242, 243

Decrease TGF-b1

Use of Losartan, Cozaar, Hyzaar; use of pentoxifyllene

209, 244

Reduction of MMPs

Doxycycline (Periostat)

Other tetracyclines

245, 246

9. Stabilizing Key Arenas of Conflict: Focus on Bone Integrity, Biomarkers, Etc

The old expression of "cross one bridge at a time" is valuable in approaching life's problems. In the various arenas encountered by the patient, partner, and physician in dealing with prostate cancer, this philosophical approach is sound advice. The crux of integrative or holistic medicine is the realization that fixing one aspect of health affects multiple areas--everything is interconnected. This is especially true for PC-related issues.

Bone Integrity Affects the Natural History of Prostate Cancer

Bone integrity in a man with PC is often ignored until the patient is symptomatic. Not until recently have the issues of osteoporosis and its relationship to PC come to the medical forefront. Not only is bone integrity of vital consequence in the matter of PC spreading to the bone, but also in the realization that bone loss through resorption can lead to bone pain, compression of the bones of the vertebral column, and fracture of a weight-bearing bone in the hip or other bones affecting function. Such complications demand immediate attention and the need for surgical and/or radiation treatment. Frequently, the patient requires strong pain-killing medications. Such adverse occurrences clearly detract from the quality of life of the PC survivor, his family, and friends. Putting out this new fire also diverts attention away from the primary issues of control and eradication of the PC.

We know that the main danger in PC is its ability to metastasize to the bone. The bone is a favored place when PC cells metastasize. Stephen Paget discussed this in 1889 in his essays on The Seed and the Soil:247

When a plant goes to seed, its seeds are carried in all directions; but they can grow only if they fall on congenial soil.

Paget recognized this inclination for cancer of the breast to spread to the bone. The same proclivity is found in PC. PC and breast cancer are brother/sister diseases, strikingly alike in a multitude of ways. Most physicians consider the bone a static tissue, but it is exactly the opposite. The bone is constantly undergoing change in a process called remodeling. Bone tissue is formed and lost in the processes of bone formation and bone resorption (see Figure 8). This remodeling of the bone tissue occurs every 100 days.

The dynamic nature of the bone tissue has been described in medical literature in thousands of peer-reviewed publications. Many patients and physicians are surprised to learn that the bone is extremely rich in growth factors. These growth factors have been implicated in PC growth and metastasis. Therefore, it should come as no surprise that prostate cancer cells consider the bone a haven or sanctuary--congenial soil, to use the words of Paget. The rationale of current therapies in prostate, breast, and other cancers is to stabilize the bone microenvironment so that these bone-derived growth factors (BDGF) are not made readily available to nurture PC growth, invasion, and metastasis.

 

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