The Concept of Hormesis in Cancer Therapy - Is Less More?

There has, in recent years, been a paradigm shift in our understanding of the role of the immune system in the development of cancers. Immune dysregulation, manifesting as chronic inflammation, not only facilitates the growth and spread of tumors but prevents the host from mounting effective immune defenses against it. Many attempts are being made to develop novel immunotherapeutic strategies, but there is growing evidence that a radical reevaluation of the mode of action of chemotherapeutic agents and ionizing radiation is required in the light of advances in immunology. Based on the concept of hormesis - defined as the presence of different modes of action of therapeutic modalities at different doses - a 'repositioning' of chemotherapy and radiotherapy may be required in all aspects of cancer management. In the case of chemotherapy, this may involve a change from the maximum tolerated dose concept to low dose intermittent ('metronomic') therapy, whilst in radiation therapy, highly accurate stereotactic targeting enables ablative, antigen-releasing (immunogenic) doses of radiation to be delivered to the tumor with sparing of surrounding normal tissues. Coupled with emerging immunotherapeutic procedures, the future of cancer treatment may well lie in repositioned chemotherapy, radiotherapy, and more localized debulking surgery.

The biography of the immune system and the control of cancer: from St Peregrine to contemporary vaccination strategies.

BACKGROUND: The historical basis and contemporary evidence for the use of immune strategies for prevention of malignancies are reviewed. Emphasis is focussed on the Febrile Infections and Melanoma (FEBIM) study on melanoma and on malignancies that seem to be related to an overexpression of human endogenous retrovirus K (HERV-K). DISCUSSION: It is claimed that, as a result of recent observational studies, measures for prevention of some malignancies such as melanoma and certain forms of leukaemia are already at hand: vaccination with Bacille Calmette-Guérin (BCG) of new-borns and vaccination with the yellow fever 17D (YFV) vaccine of adults. While the evidence of their benefit for prevention of malignancies requires substantiation, the observations that vaccinations with BCG and/or vaccinia early in life improved the outcome of patients after surgical therapy of melanoma are of practical relevance as the survival advantage conferred by prior vaccination is greater than any contemporary adjuvant therapy. SUMMARY: The reviewed findings open a debate as to whether controlled vaccination studies should be conducted in patients and/or regions for whom/where they are needed most urgently. A study proposal is made and discussed. If protection is confirmed, the development of novel recombinant vaccines with wider ranges of protection based, most likely, on BCG, YFV or vaccinia, could be attempted.

Is a hypothetical melanoma-like neuromelanin the underlying factor essential for the aetiopathogenesis and clinical manifestations of multiple sclerosis?

BACKGROUND: Multiple sclerosis (MS) has undergone a significant increase in incidence in the industrialised nations over the last 130 years. Changing environmental factors, possibly infections or a lack of or altered timing of them, determine the prevalence of the disease. Although a plethora of aetiological factors, clearly evident in a group of children with MS, appear relevant, there may nevertheless be a single factor essential for the aetiopathogenesis and clinical manifestation of MS. DESCRIPTION AND DISCUSSION: This hitherto unknown factor is postulated to be a 'melanoma-like neuromelanin' (MLN) dependent on the activation of a gene for syncytin-1. An involvement of MLN could explain the diverse findings in the epidemiology, immunology and pathology of MS, requiring a consideration of a complex infectious background, the human leucocyte antigens, as well as cosmic radiation causing geomagnetic disturbances, vitamin D deficiency, smoking, and lower levels of uric acid. SUMMARY: In principle, the MLN-based concept is a unifying one, capable of explaining a number of characteristics of the disease. To date, MLN has not been addressed in studies on MS and future work will need to be done on human patients, as there is little or no neuromelanin (the precursor of MLN) in the animals used as experimental models in the study of MS.

Paradigms in multiple sclerosis: time for a change, time for a unifying concept.

It has recently been suggested that, rather than being an autoimmune disease, multiple sclerosis (MS) is an example of a neurocristopathy, a pathological process resulting from a faulty development of the neural crest. Whilst several characteristics of the disease suggest a neurocristopathy, other aetiological factors require consideration, including hygiene-related factors that alter the immune responses to common pathogens resulting in an eclipse of immune reactivity that could protect against MS, the possible role of human endogenous retroviruses (HERVs) in pathogenesis and autoimmune phenomena, HLA polymorphism, vitamin D levels before and after birth and immune repair mechanisms. A postulated aetiological factor in MS, associated with altered vitamin D metabolism and abnormal HERV expression, is a long-lasting disturbed redox regulation in the biosynthesis of a melanoma-like melanin pigment. Although intensive further studies on melanin pigments in nerve tissue in MS are required, the known properties of a pathological form of such pigments in melanoma could explain a number of observations in MS, including the impact of light, UV-light, and vitamin D, and could explain the clinical manifestations of MS on the basis of an oscillating process of oxidative charge and discharge of the pigments and a threshold phenomenon with a change of the quasi-catalytic function of the pigment from destroying reactive oxygen radicals or species to transforming them to more harmful long-persisting highly reactive species. Taken together with the consequences of an adaptive process in partly demyelinated neurons, resulting in an increase in number of mitochondria, and the impact of stressful life events, these conditions are necessary and sufficient to explain the disease process of MS with its spatial (plaques) and temporal (attacks and remissions) characteristics. This suggested unifying concept of the pathogenesis of MS may open perspectives for prevention, diagnosis and therapy. In particular, prevention may be achieved by vaccinating against Epstein-Barr virus in early childhood.

Tuberculosis and tubulointerstitial nephritis: an intriguing puzzle.

Classical renal tuberculosis is a well-known cause of urinary tract scarring and calcification, and sometimes renal dysfunction. In the past two decades there have been reports, particularly from the United Kingdom among immigrants from the Indian subcontinent, of a more insidiously progressive form of renal disease. Ultrasound shows small smooth kidneys, and histology reveals tubulointerstitial nephritis including granulomas but not acid-fast bacilli. Evidence is mounting that the underlying cause may be tuberculosis, but the mechanism remains obscure.

Viewpoint: Scientific dogmas, paradoxes and mysteries of latent Mycobacterium tuberculosis infection.

Worldwide, there are nearly 10 million new cases of active TB and 1.8 million associated deaths every year. WHO estimates that one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), forming a huge latent Mtb global reservoir. This renders the prospect of ever eliminating Mtb from the human race almost impossible. Several controversial issues regarding host-pathogen interactions and existing prevention and eradication strategies for latent Mtb infections need to be critically re-examined. In this viewpoint, widely held assumptions on Mtb latency and isoniazid monotherapy and chemoprophylaxis are challenged. We highlight the need for future research to resolve these issues and to develop evidence-based strategies for better understanding of equilibrium and escape of Mtb in the human body, eventually leading to global recommendations for elimination of the latent Mtb state through informed policy and practice. Until such strategies and policies are realized, WHO and TB experts will have to settle for global TB control rather than eradication.

Is the eradication of tuberculosis 'yesterday's ambition' or 'tomorrow's triumph'?

Tuberculosis (TB) remains a serious infectious disease continuing to cause around 1.8 million deaths annually. The great paradox is that despite the availability of effective treatment for the past 60 years, it continues to spread relentlessly, particularly in sub-Saharan Africa due to the fuelling effect of the HIV/AIDS epidemic. It is no longer a medical epidemic, but an epidemic of injustice. Increased political and financial investment by the industrially developed nations, as well as sustained political will in the affected countries, is required to bring TB under control. It is imperative that the control should be linked to that of HIV which is also closely associated with poverty, poor housing and malnutrition. The historical, social, philosophical and political perspectives that may have influenced the failure of TB control are discussed. Once again, therefore, the question is raised--can TB be brought under control?

Tuberculosis in association with HIV/AIDS emerges as a major nonobstetric cause of maternal mortality in Sub-Saharan Africa.

Every year, approximately 250,000 African women die during pregnancy, delivery, or the puerperium. Maternal mortality rates due to infectious diseases in Sub-Saharan Africa now supersede mortality from obstetric causes. Evidence is accumulating that tuberculosis associated with HIV/AIDS, malaria, sepsis, and other opportunistic infections are the main infectious causes of maternal deaths. Screening for these killer infections within prenatal healthcare programs is essential at this stage to prevent and treat causes of maternal mortality. The combination of proven effective interventions that avert the greatest number of maternal deaths should be prioritized and expanded to cover the greatest number of women at risk, and incorporated into a "prophylaxis and treatment community package of care." The effectiveness of these "packages of care" will need to be determined subsequently. Maternal deaths from tuberculosis are now on the increase in the UK, and due diligence and watchful surveillance are required in European prenatal services.

Multiple sclerosis: are protective immune mechanisms compromised by a complex infectious background?

The immunological background of multiple sclerosis (MS) manifests as an altered reactivity against a diverse range of infections, particularly with the Epstein-Barr virus. Although this could be only an epiphenomenon of a more generalised dysfunction of the immune system in MS, it is also possible that a complex infectious background forms the basis of a specific immune dysregulation finally causing the disease. It is thus suggested that the complex infectious background bears the key for an understanding of the immune pathogenesis of the disease. It appears probable that improved standards of hygiene cause regulatory defects in the immune system, allowing the abnormal expression of human endogenous retroviral (HERV) genes. On the basis of epidemiological observations we describe how a failure of expansion or an eclipse of a subfraction of self-antigen-specific CD8(+) T cells mediating immune repair, and a deleterious mode of action of HERV gene products, could underlie the pathogenesis of MS.

Can prior vaccinations against certain infections confer protection against developing melanoma?

Currently available, relatively safe vaccines may help tackle this serious and increasing public health problem.

Immunotherapy for malignant melanoma--tracing Ariadne's thread through the labyrinth.

A working group (FEBIM) within the European Organisation for Research and Treatment of Cancer undertook extensive studies on the possible association of infectious diseases and the risk of malignant melanoma. These studies provided evidence that several infectious diseases and also some vaccines including the anti-tuberculosis vaccine, BCG, derived from Mycobacterium bovis, confer a significant level of protection against this form of cancer. In recent years, the importance of immunoregulatory networks in the establishment of tolerance to tumour antigens and the key role of the innate immune system in the development of such networks have been recognised. The molecular patterns of micro-organisms activate pattern recognition receptors on antigen presenting cells and determine the qualitative nature of the ensuing immune response. Bacteria in the actinomycetales family, notably members of the genus Mycobacterium, exhibit particularly powerful adjuvant activity and profoundly affect underlying patterns of immune reactivity. In particular, there is growing evidence that a heat-killed preparation of a strain of Mycobacterium vaccae is able to down-regulate patterns of immune reactivity that favour the tumour and to induce those that lead to anti-cancer immune responses. The results of preliminary clinical observations with melanoma patients, and published studies on other cancers, point to the need for more formal clinical trials.

The common mycobacterial antigens and their importance in the treatment of disease.

The mycobacteria are one of a number of genera making up the aerobic Actinomycetales. Their antigens demonstrable by immuno-precipitation methods can be divided into four groups. The group i antigens, common to all mycobacterial species, cross-react with their counterparts in animal cells, largely derived from mitochondria. Notable amongst these antigens are the heat-shock, or stress, proteins and possibly bacterial sugars. Tests of cell-mediated immunity show that people can be separated by their responsiveness in skin-test, or lymphocyte proliferation techniques, into four categories of responders. Category 1 individuals respond to all mycobacterial reagents through recognition of the group i antigens. Many chronic diseases are associated with a lack of cell-mediated responsiveness to the group i antigens, and have a raised antibody titre to them. This reflects a predominance of T helper 2 activity and reduced T helper 1 responsiveness as part of the pathogenesis of their diseases, which include chronic bacterial, viral and parasitic infections, allergies, auto-immunities and neoplasms. Packaged together, the group i antigens and the cell-wall adjuvants of selected aerobic Actinomycetales make potent immuno-modulatory reagents. An example is heat-killed Mycobacterium vaccae, useful in both prevention and treatment of disease. Treatment with such reagents results in alleviation of disease, restoration of cellular responsiveness to the common mycobacterial antigens and a decrease in antibody titres to them. This new approach to treatment for such a wide range of diseases has few disadvantageous side effects and can accompany other non-immunosuppressive therapies.

Is the risk of multiple sclerosis related to the 'biography' of the immune system?

Multiple sclerosis (MS) with onset in childhood offers a unique opportunity to study the infectious background of this disease but the immune reactions against infectious agents in such children have only recently been investigated. These and other epidemiological studies strongly implicate involvement of one or more infectious agents in the aetiology of MS, with Epstein-Barr virus (EBV) being the prime candidate. Rather than being the actual cause of MS, it is more probable that these agents are involved in the development of immunoregulatory pathways. These pathways, if disturbed by hygiene-related factors including an altered sequence of infections, may generate and maintain a deficit within the immunological network that facilitates, to particular early events in the development of MS, preceding the onset of MS disease by years or a decade. A framework that can serve as a guide for further epidemiological, immunologic and molecular biologic investigations is formulated. This approach may shed light on the complex natural history of MS and may lead to rational preventive and therapeutic strategies. It is possible that, in the future, MS could be prevented by vaccination against EBV in early childhood; the framework is of relevance to the design of an appropriate type of vaccine.