~Prostate Cancer, part 9 - Anti-angiogenesis Treatments and Dietary Changes

Stopping Supply Lines to the Enemy: 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. To add insult to injury, the very environmental condition--hypoxia--that 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 colocalized.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 below.

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

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

  • Bone Integrity
  • Evaluation of Bone Status Using QCT Versus DEXA
  • T Score
  • QCT Testing
  • Cardiovascular Risk and Alzheimer's Disease
  • Clinical Aspects of Bone Integrity

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. 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.

The Difference Between Evaluation of Bone Status Using QCT Versus DEXA

Emphasizing the importance of the bone microenvironment in PC appears justified because there is a strong correlation with osteoporosis and osteopenia, as determined by bone mineral density examinations, at the time of diagnosis of PC.

In a report by Smith et al., osteoporosis was present in 63% of men at the time of diagnosis of PC, prior to any therapy. An additional 32% of men, in this same study population, had osteopenia.248 In this landmark paper, the investigators evaluated DEXA bone mineral density testing and compared it to quantitative computerized tomography (QCT) bone mineral density testing in the same patients. A significantly greater percentage of men were found to have osteoporosis using the QCT methodology than the DEXA approach. DEXA bone mineral density evaluation picked up osteoporosis in only 5% of men. Therefore, using QCT technology, abnormalities in bone density were found in 95% of men compared to 34% of men with DEXA.

Studies done by Strum and Scholz have confirmed the results of Smith et al. We found either osteoporosis (50%) or osteopenia (50%) in 100% of the men we studied with QCT. In the same men, using DEXA, we found only 5% with osteoporosis and 50% with osteopenia.249 A reasonable question is "why are there such differences in the two techniques?" The DEXA scan may read degenerative changes involving bone and joint tissues and calcium deposits within blood vessels as bone density.250-254

DEXA Scanning Underestimates the Occurrence of Osteoporosis in Men with PC

The data from two separate groups evaluating DEXA versus QCT bone mineral density (done at the same time in men with PC) are strikingly alike. The evaluation of bone density with QCT should be a routine tactic in our goal to achieve and maintain bone integrity.

Clinical Study   Osteopenia   Osteoporosis   Totals
Smith et al.248            
DEXA   29%   5%   34%
QCT   32%   63%   95%
Strum et al.249            
DEXA   50%   5%   55%
QCT   50%   50%   100%

The T Score Determines Your Status and Risk of Fracture

The definitions used in the bone mineral density reports that are valid for men or women relate to the T scores. These reports are confusing even to radiologists who are experts in this field. The Z score is often relayed to patients and physicians in the radiology report as the final diagnosis or impression. The Z score compares the findings of the bone density exam, be it QCT or DEXA, with an age-matched population. This is of little actual value because what we are doing is comparing possible pathological findings in a patient with known problems with osteoporosis or osteopenia in a general population of similar age. If I were 70 years old, I would not feel reassured that I am like most other 70-year-olds (who may also have osteoporosis or osteopenia) and therefore I am considered to be normal. I want my bone density to be compared to that of someone with healthy bone tissue that is not likely to fracture, or to release BDGF (bone derived growth factors), which may initiate prostate cancer, stimulate its growth, or have a permissive action on bone metastases.

Therefore, it is the T score that is, or should be, the benchmark in bone mineral density (BMD) evaluations. The T score is based on World Health Organization (WHO) population studies that indicate how your bone density compares to that of a healthy 30- to 35-year-old (woman). There have been no T score determinations set up for men. If the BMD is exactly 1 standard deviation below that which is considered to be normal bone density for a 30- to 35-year-old woman, the patient's T score is minus (-) 1.0. If the BMD is one half of a standard deviation above what is considered normal for a 30- to 35-year-old, the T score is +0.5. More than 1 standard deviation below normal is considered to be the cut-off level to define abnormality. Therefore, if you have a T score of -1.1 or less, you have at least osteopenia. If the T score falls between -1.1 and -2.5, you are still in the range of osteopenia. Once below -2.5, the patient falls into the category of osteoporosis. The fracture risk doubles for each standard deviation below the normal T score.255 Therefore, a person with a T score of -2.0 has twice the chance of fracturing a bone compared to a person with a T score of -1.0.

Osteoporosis is rampant in men newly diagnosed with PC. That is clear from previously cited studies. In light of the knowledge that bone loss occurs during treatment with any therapy that lowers male hormone, the PC patient undergoing almost all forms of ADT is in double jeopardy of having abnormal bone density and a serious risk of osteoporosis. Add to this knowledge the fact that bone loss through the process of resorption may be stimulating the PC, and the issue of bone integrity becomes paramount.

In our military analogy, the stabilization of a strategic area is associated with words such as bunker, fortress, citadel, and stronghold. In the context of prostate cancer (PC), the bone tissue has to be regarded as a strategic area and must be stabilized, fortified, and brought to the status of a stronghold if we are to optimize our care of the PC patient.

Resources for QCT Testing

Improving bone integrity mandates that we first assess bone integrity status to obtain a baseline. BMD evaluation and the value of the QCT technique has been emphasized in the preceding paragraphs. Since QCT technology is not readily known to most physicians, it is important that patients and partners share these new findings and seek out radiology facilities that have QCT bone densitometry equipment. Two references for sources of QCT testing are Mindways, Inc. and Image Analysis. Telephone numbers and websites for these nationally based organizations are Mindways, (877) 646-3929 (www.qct.com), or Image Analysis, (800) 548-4849 (www.image-analysis.com).

Importance of Bone Integrity Extends to Cardiovascular Risk and Possibly Alzheimer's Disease

Studies have shown a relationship of abnormal bone density with an increased risk of cardiovascular disease.256,257 It has been the observation of many that the loss of bone matrix detected by measurements of bone mineral density appears to relate to the deposition of calcium in arteries such as the coronaries, aorta, and femoral arteries. The loss of calcium from the bone matrix is a characteristic finding during excessive bone resorption. Hypothetically, it is reasonable to consider that calcium lost from the bone matrix may be pathologically deposited in blood vessels as well as associated with calcifications elsewhere, such as kidney stones, gall stones, and prostatic calculi. In fact, correlations between osteoporosis and an increased risk for kidney stone development have been reported.

An improvement in bone density with treatments that are designed to prevent kidney stones have likewise been reported.258,259 Studies have shown that bisphosphonate compounds [such as alendronate (Fosamax®)] not only improve bone mineral density but also decrease a substance known as osteopontin, which has been implicated in kidney stone development.260 Other studies have presented this unifying concept and have even linked bone loss and kidney stones with hypertension (high blood pressure).261

A biological marker involved in PC, especially androgen-independent PC, is interleukin-6 (IL-6).262-264 IL-6 is a cell product that stimulates the maturation of osteoclasts, the cells that are major players in the breakdown (resorption) of bone. IL-6 is produced by osteoblasts265 and stimulates the mature osteoclasts to break down bone. IL-6 has been identified as an inflammatory cytokine that is likely to play a major role in Alzheimer's disease (AD). Therefore, the emphasis on bone integrity is of potentially great magnitude. Maintaining bone integrity can now be seen to play a role in the following:

  • Prevention and treatment of osteopenia or osteoporosis
  • Decrease in cardiovascular disease
  • Reduction in kidney stone formation
  • Minimization of release of bone-derived growth factors that can stimulate prostate or breast cancer
  • Prevention of Alzheimer's disease

This again points out that a holistic approach to medicine is vital to our understanding of unifying concepts involved in both health and disease. The hip bone is connected not only to the thigh bone, but also to the heart, kidneys, prostate, breast, and brain.

AD is considered to be an inflammatory disease of the brain associated with the deposition of beta amyloid material. In prior discussions, the importance of the eicosanoid pathways was detailed and the role of the inhibition of AA formation and the prevention of metabolites of AA such as PGE2 and 5-HETE by dietary changes and by the use of EPA and DHA were stressed. COX-2 inhibitors that prevent AA metabolism to PGE2 have been shown to be associated with a decreased incidence of AD. Even nonselective COX-2 inhibitors such as ibuprofen (Motrin) are now shown to have a protective effect against the development of AD.

There are studies that show that all of these pathways are integrated in PC. COX-2 expression and PGE2 secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. An upregulation of PGE2 by IL-6 in a human cell line of PIN has been demonstrated. PGE2 further stimulates IL-6 soluble receptor release and other complex intracellular functions (gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity).266 These events, induced by PGE2, lead to increased PIN growth. Conversely, the use of a selective COX-2 inhibitor (e.g., Celebrex) decreases cell growth. Moreover, PIN cell growth stimulated by PGE2 was nullified by adding antibodies to IL-6. The authors concluded that increased expression of COX-2/PGE2 contributes to PC development and progression via activation of the IL-6 signaling pathway.

It should therefore come as no surprise to find that a study of animals fed diets varying in the ratio of AA to EPA reported that (1) higher AA-EPA-ratio diets led to findings of increased PGE2 production in the bone; (2) higher PGE2 in the bone was associated with increased bone resorption; and (3) lower AA-EPA ratios (reflecting higher intake of EPA) were associated with bone formation and decreased PGE2 concentrations.201

There is no doubt that the signaling pathways of communication between a PC tumor cell and bone (with osteoblasts and osteoclasts) are multidimensional.

Clinical Aspects of Bone Integrity in the Treatment of PC Patients

The importance of bone integrity has been discussed in multiple conferences directed at the PC survivor and the physician specifically interested in PC. In 1997, I spoke about how "Bone Integrity Affects the Natural History of Prostate Cancer" at the University of Washington as part of the Northwest PC Forum organized by PC survivors. Since that time, there has been a significant increase in the number of publications and discussions on this topic. Many of the salient points relating to the evaluation and treatment of bone integrity can be found on the PCRI website at www.pcri.org. In addition to numerous articles written by me in the PCRI newsletter Insights, there is also a PowerPoint presentation on this subject that can be downloaded without charge. In general, the main issues that still need a greater focus of attention include the following:

  • Every man with PC and most likely every apparently healthy man aged 45 or over should be evaluated for osteoporosis and osteopenia.
  • Significant bone loss in PC patients is underestimated by the use of DEXA scanning and should be evaluated with QCT bone density study instead.
  • Bone resorption, and its correction, are easily evaluated by using a sensitive biomarker, as a biological endpoint (BEP).

The biological marker most sensitive to evaluate excessive bone resorption in PC appears to be the Pyrilinks-D (free deoxypyridinoline or free Dpd). Dpd levels can be obtained from the second urine sample of the patient's day. This test is inexpensive and is an excellent tool to monitor the biological endpoint of bone resorption activity. In men, a normal value for Dpd is less than or equal to 5.4 (nanomoles Dpd/nanomoles creatinine) using the Metra Biosystems assay and up to 6.6 using the assay from Quest Laboratories.

In men, if the free Dpd exceeds the upper limit of normal, it is indicative of excessive bone resorption. This finding may be secondary to underlying PC in the bone or secondary to increased bone resorption due to ADT or illnesses such as diabetes, hyperthyroidism, Paget's disease of the bone, or hyperparathyroidism.

If the Pyrilinks-D level is abnormal, it should be corrected with the use of combination therapy employing a bisphosphonate compound, a calcium-containing bone supplement, and Rocaltrol (synthetic vitamin D). The most active oral bisphosphonates are Fosamax and Actonel. The bone supplement is best taken in the evening between dinner and bedtime. Studies have shown that the administration of calcium in a bone supplement will reduce bone resorption by up to 20%, but only if it is administered in the evening.269 This is apparently due to a circadian rhythm involving bone formation and bone loss.

The use of Rocaltrol (calcitriol or 1,25-dihydroxy vitamin D3) requires a prescription. It is not to be confused with ordinary vitamin D3. There are an increasing number of articles relating to the use of standard dose270 or high dose calcitriol,271 used either alone or with chemotherapy such as Taxotere272 in combination with bisphosphonates to slow the doubling time of PSA and dramatically reduce PSA levels. This holds great promise for the PC survivor.

When bone resorption is halted, and the net effect favors bone formation, it is critical that not only sufficient calcium be available to restore bone density, but also other ingredients necessary for healthy bone formation. These include magnesium, boron, and silica, as well as vitamin K. The nature of the calcium salt used in these preparations is also of major significance, because calcium carbonate is not well absorbed in older patients when gastric HCL production is decreased.

Calcium citrate, bisglycinate, and microfine calcium hydroxyapatite should be used preferentially. Two excellent comprehensive bone supplements include Bone Assure from Life Extension Foundation and Bone Up from Jarrow. It is important for the PPP team to understand the importance of these substances in bone physiology and their interactions with other cellular processes.

Continued . . .

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