Trastuzumab

During my 29 years of work as a hospital pathologist, I conservatively estimate I assumed the responsibility for diagnosing over 75,000 malignant neoplasms and followed the clinical course of many of those cases. That experience was rewarding. It gave me a clear sense of the biology of diverse cancers, as well as the clinical outcomes achievable with the mainstream therapies. During the last two decades, my colleagues at the Institute and I participated in the clinical management of over 2,000 cases of cancer. That experience has been disconcerting, largely because it was not possible to clearly delineate the long-term efficacy of our integrative therapies. Most of those patients concurrently received immunosuppressive therapies--chemotherapy, radiotherapy and others--that countered the integrative oxystatic therapies which we prescribed. Another common problem has been the financial burden of integrative therapies on patients, since insurance carriers nearly always refuse to cover such therapies, seriously compromising the continuity of care.

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Fortunately, there has also been a subgroup of about 60 self-selected, well-informed, highly-motivated, and strong-willed individuals who assumed the primary responsibility of the control of their own cancers. They have been under our care for two to twelve years. Though limited, my experience with this small subgroup has been richly rewarding. I write this article to share my views of the biology of cancer and responses to integrative therapies based on insights they gave me, as well as on personal pathologic, clinical, and research findings. In my effort, I have looked at the problems of cancer through the prism of oxygen homeostasis because, as I explain below, oxygen drives all host defense responses to malignant neoplasms. From that perspective, I succinctly state my conclusion as follows:

The long-term outcome in unresectable cancer is primarily determined by how well oxygen homeostasis can be achieved and maintained. The benefits of soy and other phytofactors, with or without therapies that modify specific molecular and genetic pathways, are often substantial in the sense that such therapies can alter the behavior of cancer cells for variable periods of time until oxystatic therapies begin to take hold.

Oxidative Injury and Cancer

In 1995, I put forth my view that accelerated oxidative injury is the common denominator in all known factors implicated in carcinogenesis. Furthermore, unrelenting oxidative stress from any and all causes is the single most important mechanism for sustaining and perpetuating the malignant cellular replication. (1) In 2001, looking through the prism of oxygen homeostasis, I extended that hypothesis and offered the following definition of cancer:

Cancer is destructive behavior of cells incited and perpetuated by many factors that cumulatively lead to anomalous oxygen signaling. It has six other principal characteristics: (1) respiratory-to-fermentative (RTF) shift in ATP production; (2) production of prodigious quantities of organic acids--lactic acid and others; (3) creation of a cocoon of coagulated proteins around malignant cells to exclude functioning host immune cells and their soluble defense molecules; (4) uncontrolled cellular replication that disrupts local tissue architecture; (5) colonization of distant tissues in which the destructive behavior of neoplastic cells continues; and (6) under certain conditions, a cancer cell can be coaxed to alter its behavior. (2)

Coaxed to alter its behavior! From a clinical standpoint, this last attribute of cancer, in my view, should be accepted as the singular aspect of cancer of interest, both for the patient and the practitioner.

Except when early surgical excision can extirpate the cancer in toto, the long-term outcome with cancer therapies depends on how effectively oxygen homeostasis is achieved and preserved. This statement may raise some eyebrows. But this conclusion seems inescapable to me in light of personal pathologic, clinical, and research observations.

There are three treatment approaches to cancer in oncology today: (1) chemotherapy; (2) radiotherapy; and (3) newer agents that target one or more of the signaling pathways in host defenses. All three approaches seek to remove or destroy every cancer cell in the body of the patient. Notwithstanding exuberance of the oncology community, the real story of progress in cancer treatment has been--and continues to be--dismal. Consider the following quote from a 1997 report concerning national cancer statistics in The New England Journal of Medicine: "In 1986, we concluded that some 35 years of intense effort focused largely on improving treatment must be judged a qualified failure. Now, with 12 more years of data and experience, we see little reason to change that conclusion." (3)

The approach of altering the behavior of a cancer cell by focusing on issues of oxygen homeostasis, by contrast, has a different goal: to so alter the host conditions in a person with cancer that the cancer cells can be coaxed to behave in a nonmalignant fashion and/or to facilitate destruction of cancer cells by host defenses.

Thiosphaera pantotropha

Thiosphaera pantotropha is a metabolic two-timer--highly skillful in extraction of energy from sewage when oxygen is essentially absent, as well as when it is available. (4-6) First identified in 1983 in sewage plants, T. pantotropha energizes itself by robust metabolism of sulfides and thiosulfate, using nitric oxides instead of oxygen. When oxygen is available, it switches to aerobic metabolism and efficiently extracts energy from a wide array of inorganic substrates by aerobic respiration. Evidently, the bug is wise in the ways of managing its genetic pool to serve dual roles under changing conditions of oxygen availability. Indeed, in sewage plants, bursts of oxygen are introduced periodically to invigorate this microbe for enhanced sewage treatment. It is noteworthy in this context that there are many other microbial metabolic two-timers.

A cancer cell, like T. pantotropha, is also a metabolic two-timer, but with a difference: it survives in the presence of oxygen but thrives in its absence. The singular challenge in the field of cancer--in my view--is this: Can we create oxygen conditions in the body that coax a cancer cell to relinquish its infatuation with the respiratory-to-fermentative (RTF) shift, and revert back to its human respiratory mode of ATP generation with a fermentative-to-respiratory (FTR) shift? In other words, can the predominantly glycolytic metabolism mode of a cancer cell be switched to the physiologic respiratory ATP energetics of a healthy cell, fundamentally altering its energetic behavior? That is a tantalizing possibility. But, what may be realistically hoped for here? I see limited value of chemotherapeutic agents in this endeavor. By contrast, in the future I see much potential in the clinical benefits of antibodies directed against signaling molecules that sustain and perpetuate malignant cell replication. Some notable examples of such drugs are: (1) imatinib (Gleevec, a protein-tyrosine kinase inhibtor) Bcr-Ab1 tyrosine kinase; (2) gefitinib (Iressa, an inhibitor of intracellular phosphorylation of several tyrosine kinases) which binds epidermal growth factor; (3) trastuzumab (Herceptin, a DNA-derived humanized monoclonal antibody) which binds with the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2); (4) rituximab (Rituxin, a chimeric murine/human monoclonal antibody) which binds to CD20 antigens; (5) Avastin which targets angiogenesis; and others.

Altering the Behavior of Cancer Cells: Fermentative-to-Respiratory (FTR) Shift

Returning to the core issue of the possibility of coaxing cancer cells to a fermentative-to-respiratory (FTR) shift--return from glycolytic metabolism back to physiological respiratory ATP production--I cite the example of well-differentiated adenocarcinoma of endometrium that arises in severe atypical endometrial hyperplasia in young anovulatory females. Pregnancy in many such cases so alters the endometrial microecology that no sign of endometrial malignancy can be seen years later. Evidently, in such cases conception does not physically eradicate every single cancerous endometrial cell. Rather, gestation alters the behavior of malignant cells.

The FTR shift, of course, is also seen in other types of cancer. I have been most impressed by a group of 28 patients with biopsy-proven

prostatic adenocarcinoma whom I managed with primary focus on direct oxystatic therapies (described in Part II of this article) for one to 14 years. Most of them did not receive any synthetic hormonal intervention. Some of them received such treatment for short periods of time. Many of them used soy-derived and other phytofactors intermittently. They have shown no clinical (including direct rectal palpation of tumor) or laboratory evidence of progression of disease with therapies designed to maintain oxygen homeostasis and redox equilibrium. It has been clear to me that the prostatic lesions diagnosed histologically as cancers did not metabolically behave like malignant neoplasms. (I might add here that some other patients did not fare so well.)

Spontaneous Remissions

In 1974, I received a large basin full of resected ovarian cancer involving large segments of omentum. Histologically, the tumor was a poorly differentiated, high-grade adenocarcinoma. In 1994, I received smears prepared with a fine needle aspiration (FNA) biopsy material obtained from a pelvic mass in that patient for cytologic diagnosis. The cellular morphology of 1994 tumor was found to be identical to that of 1974 cancer. Later I learned from the surgeon who had performed the 1974 procedure that a CAT scan done about four years earlier had revealed the existence of the pelvic tumor. He had elected to 'let the sleeping dogs lie' since the patient had been clinically asymptomatic for years. The FNA was performed by his younger associate who was not fully aware of the considerations of the older surgeon. All experienced pathologists recall many such cases. What may we make of such cases?

A very large number of cases of spontaneous regression of histologically proven cancer have been meticulously documented. (7) I believe that occurs in most, if not all, cases because changes in cellular microenvironment coax the cancer cells to relinquish their two-timer habits, and stay faithful to respiratory ATP production.

In 1949, the American Journal of Obstetrics and Gynecology reported a highly negative charge on the cancer cells of the uterine cervix. (8) Ten years later, Science magazine reported control of cancer by normalization of the surface charge of cancer cells in mice. (9) Regrettably, those enormously significant leads were not followed. Why? Because in the United States, the pharmaceutical industry determines which research leads are funded and which ones are killed. And, of course, there are no drug dollars to be made by controlling cancer by normalizing cancer cell surface charges.

Can the cellular energetics in cancer also be influenced and restored to normalcy with an electromagnetic approach? Nicolas Tesla clearly thought so, though, to my knowledge, he never treated any cancer that way. Some other researchers have employed it with variable results. I have personally seen some cancers respond to Tesla electrotherapeutics. However, I do not have sufficient follow-up data to draw any definitive conclusion about the long-term efficacy of that approach.

Do Cancer Cells Induce Respiratory-to-Fermentative Shift In Non-Cancer Cells?

The full impact on oxygen homeostasis of non-cancerous cells in close vicinity of cancer cells is seldom fully appreciated in discussions of cancer biology. In my view, this is a crucial issue when the goal is altering the behavior of malignant cells. Cancer cells produce prodigious amounts of organic acids that cause incremental oxidative-dysoxygenative stress on non-malignant cells in their microenvironment. It is to be entirely expected that unrelenting oxidative-dysoxygenative will eventually induce a RTF shift in non-cancerous cells as well--in the process 'metabolically de-humanizing' them, so to speak. Evidently, cancer cells thrive in oxidative-dysoxygenative conditions, whereas host cells attempting to cordon them off are suffocated by those microecologic conditions. Thus, in the battle between cancer and non-cancer cells, the outcome does not merely depend on the genomic characteristics of malignant cells but also on metabolic resilience of the host cells. I believe this explains a common observation in integrative practices: Many patients with cancer who clinically do well with vigorous adherence to integrative management programs (that preserve oxygen homeostasis and redox equilibrium) deteriorate rapidly when they abandon such therapies.

Warburg Was Right, Warburg Was Off the Mark

The German chemist Otto Warburg clearly and emphatically designated the fermentative metabolism of a cancer cell as its fundamental metabolic lesion. That, of course, was an enormous contribution to our understanding of cellular energetics of cancer. I begin my definition of cancer with the fermentative aspect of the metabolism of a cancer cell to recognize that contribution, as well as to emphasize the crucial clinical significance of Warburg's assertion.

Warburg took pains to underscore his notion of the irreversibility of the metabolic (glycolytic) shift in cancer. That notion--it seems to me--is open to question. Warburg wrote: "For cancer formation there is necessary not only an irreversible damaging of respiration but also an increase in fermentation--indeed, such an increase of the fermentation that the failure of respiration is compensated for energetically." (10)

Fully in awe of Warburg's contribution to the field, here I express my opposition to his view of irreversibility of cancer. My primary argument against Warburg's view is the experience of many of my patients who have lived--and are living--long healthful lives with oxystatic therapies, and without surgery, radiotherapy, or chemotherapy, years after the initial diagnosis. Similar cases are not unknown to integrative clinicians.

I now underscore my definition by clearly identifying cancer as a "cellular behavioral disorder." To underscore the core metabolic derangement in cancer, I state that all dynamics of a cancer--first and foremost--are driven by deranged oxygen metabolism, designated as dysoxygenosis. This view of cancer evidently, is at variance with a multitude of others that hold as common denominators the issues of genes and cascades of regulatory and downstream effectors initiated by mutated genes. (11-15)

In 1931, Warburg was awarded the Nobel Prize in medicine for his discovery of oxygen transferring enzymes. Thirteen years later, he won a second Nobel Prize for his delineation of hydrogen transferring enzyme. (He was prevented from receiving that prize for being Jewish by the Hitler regime.) During that period he recognized the energetic shift in malignant cells alluded to earlier. (16-18) The following two quotes from his writings are noteworthy for the succinctness of description of his view of cancer: "Since the respiration of all cancer cells is damaged, our first question is. How can the respiration of body cells be injured? Of this damage to respiration [of cancer cells], it can be said that at the outset that it must be irreversible, since the respiration of cancer cells never returns to normal." (18)

Warburg went on designate the shift in the oxygen-related energetics of a cancer cell as the prime cause of cancer, to which all secondary causes contribute. Consider the following quote from a special lecture he delivered on June 30, 1966, at the meeting of the Nobel laureates at Lindua, Germany: "There are prime and secondary causes of diseases.... Cancer, above all other diseases, has countless secondary causes. Almost anything can cause cancer. But even for cancer, there is only one prime cause." (19)

Warburg, of course, was referring to oxygen in the above quote. The implications of Warburg's notion of the fundamental difference between the metabolism of a cancer cell and a normal cell were both profound and clear. It meant that oxygen-related issues must be in the centerfield in all considerations for treating cancer. Initially, Warburg's seminal discovery sparked intense interest about the potential of oxygen therapeutics for the treatment of malignant neoplasms among a large number of European and American clinicians. (20-22) Those therapies included: (1) direct oxygenative (nasal oxygen, oxygen baths, and others); and (2) indirect bio-oxidative therapies (intravenous infusions of ozone and hydrogen peroxide).

The Oxidative-Dysoxygenative Model of Cancer

In 1998, soon after I developed the core concept of dysoxygenosis, (23) it became evident to me that one cannot separate redox dynamics from oxygen homeostasis in cancer any more than one can do so in other disorders. In essence, the respiratory-to-fermentative shift in cancer--the core tenet of Warburg's theory of metabolism of malignant tumors--is primarily triggered by oxidative injury to cellular replication and differentiation pathways. (2) That conclusion seemed inescapable as I surveyed a large body of data concerning redox dynamics of neoplastic cells. I proposed that all known cancer risk factors and existing theories of cancer can be brought together by the simple notion that oxidative injury is the common denominator. Furthermore, in chronic disorders systemic and/or local oxidosis mediates its most destructive effects through the systemic and/or local dysoxygenosis it sets the stage for. Thus, the oxidative-dysoxygenative (OD) model of cancer evolved as an extension of my earlier hypothesis of the primacy of oxidative injury in the causation and perpetuation of cancer. (2)

There are five critical issues in this context:

1. A major strength of the OD model of carcinogenesis--in my view--is that it is fully consistent with the focus of Warburg on glycolysis; of Pauling on antioxidants; and of others on environmental, viral, and genetic factors in considerations of etiology and treatment of cancer.

2. The OD model of cancer brings into sharp focus how dysoxygenosis alters the milieu of host cells in vicinity of malignant cells. (Cancer cells metabolically dehumanize the surrounding cells, so to speak, by inducing respiratory-to-fermentative shift in them, further fanning the flames of cellular dysoxygenosis).

3. The OD model of cancer has a strong explanatory power for several clinical phenomena concerning the biologic behavior of malignant neoplasms, such as long periods of quiescence of tumors, spontaneous regression, and explosive growth of cancers after severe oxidative-dysoxygenative stresses, such as those associated with acute illnesses and discontinuation of strong support.

4. In contrast to Warburg's notion of irreversibility of the glycolytic metabolism of cancer, the OD model of cancer recognizes the possibility of restoration of oxygen homeostasis in cancer cells with the resumption of predominantly oxygenative respiratory mode of ATP energetics.

5. Most important, the OD model serves as a complete model for designing rational and scientifically sound integrative management plans for good long-term clinical results with a sharp focus on oxystatic therapies.

Genetic Modulation of the Behavior of Cancer Cells

A large number of genes have been implicated in carcinogenesis. Oncogenes promote carcinogenesis while suppressor genes prevent it. (24) Cancer susceptibility genes have been divided into two categories: gatekeepers and caretakers. Gatekeepers control cell proliferation and demise, whereas caretakers repair damaged DNA sequences and prevent DNA strand breakage, translocation, and aneuploidy. (25-27) Impaired gatekeeper function sets the stage for uncontrolled cellular proliferation and neoplastic transformation, while suppression of caretakers results in genetic instability and increased risk of carcinogenesis.

To cite two specific examples, the ras oncogene is activated in about 30-40% of cancers, whereas the p53 suppressor gene is nonfunctional in a variable number of patients with cancers arising in various body organs. Those findings led to simplistic thinking--and irrational exuberance--about the possibility of curing cancer either by switching off the oncogenes or switching on the suppressor genes. Biology seldom, if ever, yields to such enthusism. Not unexpectedly, no results have been achieved in the field to date. Genes form an enormous web in which every change in one site brings forth broad change in every other site. In 2000, in Oxygen and Aging I offered the explanation why gene modulation will never provide the full answer to the problem of cancer with the following words: Genes are living beings. They talk and listen to each other. Their language is living and creative. They do not recognize simplistic mechanical models of replacing worn-out materials with spare parts. Genes read their environment and adapt. But humans need a living environment to flourish, hence the core importance of optimal oxygen metabolism for their function. (28)

Gene therapies in the future may yield some short-term results but--in my view--not to the degree that patients and practitioners will be able to neglect the essential issue of oxygen homeostasis without sacrificing the chances of good long-term control of cancer.

Acetylation, Methylation, and Cancer Control

The structural and functional integrity of DNA is profoundly influenced by enzymes involved with acetylation, deacetylation, methylation, and demethylation. Recent advances in those enzymatic dynamics have brought forth a misguided enthusiasm about curing cancer by controlling those dynamics, reminiscent of earlier misguided enthusiasm concerning oncogenes and suppressor genes.

Since deacetylase inhibitors do not add or delete nucleotide sequences in DNA, theoretically histone deacetylase inhibitors are capable of altering the behavior of cancer cells by "normalizing DNA." Indeed, one such inhibitor, FK228--a copy of a peptide isolated from a soil bacterium, has shown limited initial results in some patients with cutaneous T-cell lymphomas. (29) It seems safe to predict that additional experience will show such results to be temporary. Such is the complementarity and contrariety in genomics. (See Nature's Preoccupation With Complementarity and Contrariety, the first volume of The Principles and Practice of Integrative Medicine (30) for detailed discussion of the subject.)

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As for methylation/demethylation reactions, it has been claimed (with supportive data) that some natural compounds in human blood and urine can reverse abnormal methylation and mutation of carcinogeneic genes. (31) It is likely that this approach will also yield some clinical benefits. Again, as in the case of acetylation/deacetylation dynamics, it seems safe to predict that additional experience will show such results to be temporary.

In closing, there are some promising leads in cancer therapies which may yield variable clinical results. Among those are empirically tested phytofactor formulations, such as fermented soy concoctions, which are likely to prove clinically more valuable than therapies directed to modulation of cancer genomics. However, the long-term health and survival of persons with cancer--it seems to me--will continue to depend on how well oxygen homeostasis can be achieved and maintained.

References

1. Ali M: RDA: Rats, Drugs, and Assumptions, Denville, New Jersey, Life Span Books 1995.

2. Ali M. Carcinogenesis: The Oxidative-Dysoxygenative Model. J Integrative Medicine 2001;5:9-32.

3. Bailar JC III. Gornik HL Cancer unconquered. N Eng J Med 1997;336:1569-74.

4. Ranghino G, Scorza E, Sjogren T, Williams PA, et al. Quantum mechanical interpretation of nitrite reduction by cytochrome cdl nitrite reductase from Paracoccus pantotrophus. Biochemistry. 2000,39:10958-66.

5. Su JJ, Liu BY, Liu CY. Comparison of aerobic denitrification under high oxygen atmosphere by Thiosphaera pantotropha ATCC 35512 and Pseudomonas stutzeri SU2 newly isolated from the activated sludge of a piggery wastewater treatment system. J Apl Microbiol. 2001;90:457-62.

6. Kobayashi K, Koppenhofer A, Ferguson SJ, et al. Plse radiolysis studies on cytochrome cd 1 nitrite reductase from Thiosphaera pantotropha: evidence for a fast intramolecular electron transfer from c-heme to dl-heme. Biochemistry. 1997,36:13611-6.

7. O'Regan B, Hirshberg C, Oregan B. Spontaneous Remission: An Annotated Bibliography, 1995. Petaluma, CA. Inst of Noetic Sciences Publisher.

8. Langman U, Burr H S. A technique to aid in the detection of malignancy of the female genital tract. Am J Obstet Gynecol 1949;57:274-81.

9. Humphrey CE, Seal EH, Biophysical approach toward tumor regression in mice. Science. 1959;130:388.

10. Warburg O. On the Origins of Cancer Cell. Science 1956,309-314.

11. Ponder BA. Cancer genetics. Nature. 2001;411:336-341.

12. Taipole J, Beachy PA. The hedgehog and Wnt signaling pathways in cancer. Nature. 2001,411:349-354.

13. Blume-Jensen P. Hunter T. Oncogenic kinase signaling. Nature, 2001;411:355-65.

14. Hoeijmakers JHJ. Genome maintenance mechanisms for preventing cancer. Nature. 2001,411:366-74.

15. Liotta LA, Kohn EC. The microenvironment of the tumor-host interface. Nature. 2001;411:375-79.

16. Warburg O. Heavy Metals as prosthetic groups of enzymes, Clarendon Press, Oxford, 1949.

17. Warburg O. Oxygen, The Creator of Differentiation, Biochemical Energetics. 1966. New York. Academic Press

18. Warburg O. New Methods of Cell Physiology, 1962. Georg Thieme, Stuttgart, and Interscience Publishers, New York, 1962.

19. Warburg O. The Prime Cause and Prevention of Cancer. 1967. Wurzburg, Germany. Koncad Triltach Publishing Co.

20. Rilling S. Historical view of the developments of medical ozone therapy. KongreBbericht IOA (International Ozone Association) 7. Ozon-WeltkongreB. 9-12 September 1985; Tokyo.

21. Sunnen GV. Ozone in medicine: Overview and future directions. Journal of Advancement in Medicine 1988; 1(3): 159-174.

22. Bocci V. Paulesu L. Studies on the biological effects of ozone 1. Induction of interferon gamma on human leucocytes. Haematologica. 1990,75:510-515.

23. Ail M: Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine 1999;3:11-16.

24. Folkman J. What is the evidence that tumors are angiogenesis dependant? J Natl Cancer Instit 1990;82:4-6.

25. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 2000;100:57-70.

26. Liotta, L. & Petricoin, E. Molecular profiling of human cancers. Nature Rev. Genet. 2000;1:48-56.

27. Park, M. in The Genetic Basis of Human Cancer. 1998. (eds Vogelstein, B. & Kinzler. K. W) New York. McGraw Hill, pp205-228.

28. Ali M. Oxygen and Aging. (1st ed.) New York, Canary 21 Press. Aging Healthfully Book 2000.

29. Pickarz RL. Robey R. Sandor V. et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001;98:2865-8.

30. Ali M. The Principles and Practice of Integrative Medicine Volume I. Nature's Preoccupation With Complementarity and Contrariety. 2000. Washington, D.C. Capital University Press (in collaboration with Canary 21 Press, New York). www.cuim.edu & www.Canary21press.com)

31. Mitchell T. Unlocking the mystery of antineoplastins. Life Extension. May 2004. pp76-82.

by Majid Ali, MD

Director, The Institute of Integrative Medicine

212-873-2444 * 973-586-4111

www.majidali.com

Dr. Ali is president and professor of medicine of Capital University of Integrative Medicine, Washington, DC, and Director of the Institute of Integrative Medicine, New York. www.majidali.com. This article is adapted from Dysoxygenosis and Oxystatic Therapies, the third volume of The Principles and Practice of Integrative Medicine.

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