Apoptosis y antiapoptosis en cáncer, Alzheimer y procesos neurodegenerativos: ¿una dialéctica de contrarios? Nuevo abanico de posibilidades terapéuticas y peligros potenciales / Apoptosis and antiapoptosis in cancer, Alzheimer’s disease and degenerative processes: a dialectics of opposites? New range of therapeutic possibilities and potential dangers

Los intricados caminos de señalización intracelular en la desregulación de la apoptosis, espontánea o inducida, se han convertido en las principales dianas terapéuticas en enfermedades que van desde las neoplásicas a los procesos neurodegenerativos. A la vista de las tendencias actuales en investigación se puede afirmar que el fracaso en inducir una apoptosis selectiva en las células y tumores cancerosos (proapoptosis), y en sentido contrario, la imposibilidad de evitar la apoptosis espontánea en enfermedades neurodegenerativas como el Alzheimer (antiapoptosis), representan una raíz y árbol común para dos ramas, o áreas de la medicina, creciendo en sentidos opuestos. El enfoque aquí presentado es un intento de estimular una visión integrada de ambas ramas y áreas de investigación, oncología y neurología, en orden a mejorar la comprensión de sus naturalezas íntimas, tratando así de incrementar el entendimiento de las anormalidades básicas y clínicas de los procesos bajo estudio. A esto se puede acceder a través de un escalonamiento diferenciador de las posibilidades terapéuticas que se están abriendo en la actualidad, así como merced a una consideración preliminar de los peligros potenciales que pueden surgir en el empeño

The intricated pathways of intracellular signaling and the deregulation of cell apoptosis, either spontaneous or induced, are becoming the main molecular and therapeutic targets ranging from cancer to neurodegenerative diseases. Modern trends in research and treatment show that the failure to induce selective cancer cell and tumor apoptosis (proapoptosis), and, in the opposite direction, the failure to prevent the spontaneous apoptosis of neurodegenerative diseases, like Alzheimer’s disease, can be interpreted as problems representing two branches, or areas, of medicine growing in opposite directions. The approach here advanced represents an attempt to stimulate an integral vision of both branches or areas of research, oncology and neurology, hoping to improve the understanding of the intimate nature of the basic and clinical abnormalities under investigation. A stop by step differentiation of the therapeutic possibilities that are being opened nowadays is considered, as well as some preliminary and potential dangers raised by the very same treatment efforts

Apoptosis y antiapoptosis en cáncer, Alzheimer y procesos neurodegenerativos: ¿una dialéctica de contrarios? Nuevo abanico de posibilidades terapéuticas y peligros potenciales / Apoptosis and antiapoptosis in cancer, Alzheimer's disease and degenerative processes: an opponents dialectics? New range of therapeutic possibilities and potential dangers

Los intrincados caminos de señalización intracelular en la desregulación de la apoptosis, espontánea o inducida, se han convertido en las principales dianas terapéuticas en enfermedades que van desde las neoplásicas a los procesos neurodegenerativos. A lo visto de las tendencias actuales en investigación se puede afirmar que el fracaso en inducir una apoptosis selectiva en las células y tumores cancerosas (proapoptosis), y en sentido contrario, la imposibilidad de evitar la aopotosis espontánea en enfermedades neurodegenerativas como el Alzheimer (antiapoptosis), representan una raíz y árbol común para dos ramas, o áreas de la medicina, creciendo en sentidos opuestos. El enfoque aquí presentado es un intento de estimular una visión integrada de ambas ramas y áreas de investigación, oncología y neurología, en orden a mejorar la comprensión de sus naturalezas íntimas, tratando así de incrementar el entendimiento de las anormalidades básicas y clínicas de los procesos bajo estudio. A esto se puede acceder a través de un escalonamiento diferenciador de las posibilidades terapéuticas que se están abriendo en la actualidad así como merced o una consideración preliminar de los peligros potenciales que pueden surgir en el empeño (AU)

Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis.

Tumour angiogenesis and cellular pH regulation, mainly represented by Na(+)/H(+) antiporter exchange, have been heretofore considered unrelated subfields of cancer research. In this short review, the available experimental evidence relating these areas of modern cancer research is introduced. This perspective also helps to design a new approach that facilitates the opening and development of novel research lines oriented towards a rational incorporation of anticancer drugs into more selective and less toxic therapeutic protocols. The final aim of these efforts is to control cancer progression and dissemination through the control of tumour angiogenesis. Finally, different antiangiogenic drugs that can already be clinically used to this effect are briefly presented.

Duodenal carcinoid tumor and esophageal carcinoma associated to a high chronic intake of sodium bicarbonate. Possible pathophysiological mechanisms

Los tumores carcinoides son frecuentemente asociados a situaciones de hipocloridria de diferente etiología. Se presenta aquí un caso de dos tumores metacrónicos, un carcinoide y un cáncer de esófago, en un paciente con una ingesta crónica de bicarbonato sódico extraordinariamente elevada. Casos como este permiten integrar una gran cantidad de datos, desde básicos a clínicos, apoyando la hipótesis de que un pH microambiental crónicamente elevado, tanto en estas como en otras situaciones similares pueden, a través de mecanismos directos e indirectos, facilitar la aparición de diversos tumores malignos del tracto gastrointestinal (AU)

Implicaciones del ion hidrógeno y el antiportador Na+/H+ en la angiogénesis y antiangiogénesis tumoral / Implications of the hydrogen ion and the Na+/H+ antiports in tumor angiogenesis and antiangiogenesis

La angiogénesis tumoral y la dinámica celular de hidrogeniones (H+) han sido consideradas hasta el momento como dos entidades enteramente separadas de la investigación oncológica. Este artículo trata de exponer la evidencia existente en la actualidad, relacionando entre sí bajo un amplio concepto paradigmático, una multitud de hallazgos experimentales desperdigados. La racionalidad científica de esta perspectiva permite desvelar la existencia de una íntima conexión entre ambas áreas de investigación, abarcando desde el nivel genético al microambiental y terapéutico. Este enfoque unitario facilita a su vez nuevas líneas de investigación dirigida a la incorporación de fármacos anticancerosos de forma selectiva, sinérgica y menos tóxica en el diseño de protocolos terapéuticos dirigidos a controlar el proceso metastático. Finalmente, el conocimiento resultante de la aplicación de estos hallazgos ha obtenido esperanzadores resultados preliminares, tanto en diferentes estudios en animales como en seres humanos, los que parecen estar relacionados tanto con el control de la angiogénesis tumoral como, a su vez, con el del proceso metastático. (AU)

Curación aparente de un caso de carcinoma de ovario metastásico después de tratamiento crónico con inhibidores del antiportador Na+-H+ / Apparent cure of a case of metastic ovarian carcinoma after the chronic treatment with Na+H+ antiport inhibitors

Propósito: Descripción de un caso atípico de curación aparente de carcinoma de ovario metastático después de fracaso a la quimioterapia convencional. Material y métodos: Se investiga un caso de carcinoma de ovario libre de enfermedad más de doce años después del diagnóstico inicial y once años después de cirugía por enfermedad metastática. Resultados: La utilización crónica de altas dosis de amiloride como medida terapéutica parece haber contribuido significativamente en la evolución positiva del marcador CA-125 así como en la aparente curación de esta paciente. Conclusiones: Se discute si, tal como se ha propuesto con anterioridad, y este caso parece corroborar, el tratamiento adyuvante y/o neoadyuvante con inhibidores del antiportador Na+-H+ en ciertos casos de cáncer pueda influenciar significativamente de forma positiva la evolución clínica y el proceso metastático. (AU)

Integrating fields of cancer research through pivotal mechanisms and synthetic final pathways: a unifying and creative overview.

From cancer etiopathogenesis to selective apoptosis, from multiple drug resistance to oncogen activation and from the phenomena of spontaneous regression of cancer to certain aspects of cancer chemotherapy, all these subfields of biology and oncology research share some deep-seated, both basic and clinical, essential features and characteristics. Certain apoptosis-inducing agents of unrelated families, ranging from ether lipids to Na(+)/H(+)-antiporter inhibitors to Delta(9)-tetrahydrocannabinol all have been reported to induce selective cancer-cell death. Behind a wide array of intermediary factors and mechanisms involved in their activity, they seem to share common pivotal and/or final pathways in inducing cell death mediated by a 'pathological' accumulation of intracellular hydrogen ions as a mechanism underlying core changes in intracellular signaling pathways. An H(+)-concentration initial perspective indicates that from pathogenesis to apoptosis and multiple drug resistance, as well as oncogen activity, tumor progression and even the phenomenon of spontaneous regression, all can be interpreted from their deep (H(+))-related basic and clinical essential characteristics. This speculative review discusses the potential integration of these previously disparate subfields of cancer research, through a model which also seems to lead toward improving understanding of the fundamental nature of malignant processes. It is concluded that this synthetic and universal approach allows advancement toward a combining of different areas of oncology into deeper and more comprehensive forms of rational understanding, with the hope of paving the way towards more selective, effective and all-encompassing forms of treatment.

Integración multidisciplinaria de campos oncológicos a través de mecanismos cruciales y vías comunes. De etiopatogénesis a tratamiento / Multidisciplinary integration of oncological fields taking advantage of crucial mechanisms and shared channels. From etiopathogenesis to treatment

Diferentes campos de investigación tales como la etiopatogénesis de las enfermedades neoplásicas, la apoptosis específica de las células cancerosas, la resistencia múltiple a fármacos (RMD), la actividad de oncogenes, la neovascularización, la regresión espontánea del cáncer (REC), e incluso aspectos claves de la quimioterapia, comparten ciertos hechos fundamentales, mecanismos comunes y características, básicas y clínicas, íntimamente relacionadas. Más allá de una amplia gama de factores involucrados en una misma actividad, diversos agentes y métodos antineoplásicos comparten asimismo ciertos mecanismos cruciales y vías finales comunes de actuación. Esta revisión creativa discute, a la vez que propone, una integración jerárquica de campos previamente separados de la investigación y el tratamiento oncológico. A modo de integración científica, y a través de la creación de un lenguaje mediador entre la investigación básica y clínica, la perspectiva aquí desarrollada permite una significativa mejora en la comprensión de la esencia fundamental de las enfermedades cancerosas. El modelo aquí considerado presenta el potencial de acercar a la deseada meta de lograr una penetración lo más profunda y completa posible de la naturaleza íntima de la degeneración maligna a la vez que abre la posibilidad de nuevos y selectivos avances terapéuticos (AU)

Hydrogen ion-dependent oncogenesis and parallel new avenues to cancer prevention and treatment using a H(+)-mediated unifying approach: pH-related and pH-unrelated mechanisms.

A comprehensive examination of phenomena related to cancer is presented that is based on hydrogen ion dynamics, as viewed from the biological, biochemical, and biophysical perspective. A model is described that considers an array of cancer-associated events from oncogenesis to carcinogenesis from this perspective. The basic ideas are viewed from various aspects, ranging from the cellular level to the clinical situation. The novel types of therapeutic and prophylactic agents that result from applying these concepts are elucidated. Considerable insight into this modern approach is seen from some of the mechanisms that characterize the phenomenon of spontaneous regression of cancer.

[Combined strategy of cancerous cells: fat and protein metabolism. Conclusions (3rd of 3 parts)]. / Estrategia unitiva de las células cancerosas: metabolismo graso y proteínico. Conclusiones (tercera de tres partes).

The metabolic and biochemical program of neoplastic cells regarding carbohydrate metabolism can be extend to the rest of the metabolism. This gives a rational idea of the global strategy and thermodynamic advantages of malignant cells and of tumors in general as related to the host. A comprehensive, metaenzymatic and transbiochemical approach allows to understand some of the reasons for the limitations found along the last decades by the different chemotherapeutic attempts directed against particular enzymes overexpressed in tumor cells. This indicates that a new vision of the whole problem is preceptive. The overwhelming effects of the hydrogen ion at multiple levels indicates that an initial approach based upon this unifying principle and universal regulatory parameter may provide the initial codes, hints and hunches, of a new synthetic and unitive biological, biomedical and biophysical scientific paradigm. Initially, it already offers the possibility of a new multidisciplinary approach to the prevention and treatment of tumors such as cervical intraepitelial neoplasia.

[Lung cancer as a scar tumor: apropos a case and the possible etiopathogenetic mechanisms]. / Cáncer de pulmón como tumor de cicatriz: a propósito de un caso y posibles mecanismos etiopatogénicos.

The true existence of "scar tumors" is still being argued. A case of a 30 years old patient with an adenocarcinoma of the lung which grew on a scar secondary to a motorbike accident that happened 15 years earlier is here presented. The age of the patient, the pathology of the tumor, the radiological demonstration of the tumor progressively growing on and around a preexistent scar, as well as the long period of time that elapsed in between the initial etiological factor and the final diagnosis leave very few doubts about the "scar" origin of this neoplasia. Previously undescribed and possible etiopathogenetic mechanisms of these tumors are considered from the biochemical and energetic points of view.

[The unitary strategy of cancer cells: the hydrogen ion as a multidimensional unitary factor and carbohydrate metabolism (2)]. / Estrategia unitiva de las células cancerosas: ión de hidrógeno como factor unitario multidimensional y metabolismo hidrocarbonado (segunda de tres partes).

A systematic outlook of metabolism regarding the strategy followed by cancer cells is necessary in order to understand the thermodynamic advantages of these cells and the difficulty found in the treatment of certain malignant diseases. These features show that the present-day vision, the biochemical-analytical-fragmentary-reduccionistic approach, is not and it is not likely that it wil never be sufficient. Thus, a new paradigm of a different dimension but a the same time complementary to the previous and actual one seems necessary. Therefore, a higher and more comprehensive and outreaching vision, transbiochemical and metaenzymatic, one ecologically and macro and microenvironmentally oriented and finally synthetic and unitary one, appears mandatory. The dynamics of the hydrogen ion as applied to biological processes seems to be able to offer the opportunity to arrive to such kind of unifying comprehension through an integrated perceptive model at multiple levels of biological, biomedical and biophysical understanding.

[Unitary strategy of cancerous cells: hydrocarbon metabolism (1)]. / Estrategia unitiva de las células cancerosas: metabolismo hidrocarbonado (primera de tres partes).

A systematic outlook of metabolism regarding the strategy followed by cancer cells is necessary in order to understand the thermodynamic advantages of these cells and the difficulty found in the treatment of certain malignant diseases. These features show that the present-day vision, the biochemical-analytical-fragmentary-reductionistic approach, is not and it is not likely that it will never be sufficient. Thus, a new paradigm of a different dimension but a the same time complementary to the previous and actual one seems necessary. Therefore, a higher and more comprehensive and outreaching vision, transbiochemical and metaenzymatic, one ecologically and macro and microenvironmentally oriented and finally synthetic and unitive one, appears mandatory. The dynamics of the hydrogen ion as applied to biological processes seems to be able to offer the opportunity to arrive to such kind of unifyng comprehension through and integrated perceptive model at multiple levels of biological, biomedical and biophysical understanding.

[Homeostasis, diabetes and cancer]. / Homeostasis, diabetes y cáncer.

There is a large body of evidence to consider that the functional aspects of the metabolism of the cancer cell and hypoinsulinemic diabetes mellitus dwell at both ends of a biochemico-metabolic spectrum representing two opposite homeostatic and pathological tendencies. Furthermore, an initial homeostatic approach based up the acid-base balance and/or its hydrogen ion dynamics, systematically considered at multiple dimensions of knowledge and in different areas and fields of biomedical research, allows to reach a systematic vision and an all-comprehensive and hierarchically organized perspective for the integrated study of both malignant and non-malignant, as well as diabetic, metabolism, while at the same time opens new avenues reaching out towards a better understanding of both the etiopathogenesis of certain epithelial tumors and the chronic complications of diabetes mellitus. Besides, such a unitarian outlook may very well open new ways towards a more comprehensive understanding of the interrelationships among both degenerative processes, and from the bioenergetic to the clinical levels, hopefully leading to better preventive and treatment strategies.

The Na+/H+ antiporter in oncology in the light of the spontaneous regression of cancer and cell metabolism.

Multiple metabolic and biochemical interrelationships, as well as the most recent views on mechanisms of malignant cell growth, proliferation, and oncogen activity mediated by the Na+/H+ antiporter, can be integrated from the unitarian point of view of the dynamics of the hydrogen ion to parallel pH-related mechanisms involved in the Spontaneous Regression (SR) of some malignant tumors. Also, pH-related growth inhibitors of the amiloride series are considered as possible agents to be used in the adjuvant and co-adjuvant treatment of some human tumors as well as in the control of the metastatic process and in overcoming cancer multidrug resistance (MDR).

[Original physiopathological integration and new treatment possibilities and approaches in breast cancer]. / Inéditas integraciones fisiopatológicas y nuevas posibilidades y aproximaciones terapéuticas al cáncer de mama.

The aim of this paper is unify the physiopathological mechanisms of breast cancer proliferation and its hormonal relations. A further objective is to determine a comprehensive integration of the different hormonal therapies, considering new alternatives which are at present in developing stages. We conclude, defining and recommending further ways to focus upon and treat this disease.

Integrated etiopathogenesis of cancer of mucosal surfaces with emphasis on the digestive tract: an appraisal.

The concept of hydrogen ion concentration [H+] may become the cornerstone of an integrated understanding of the mechanisms leading to cancer of the mucous membranes, mainly of the digestive tract. From basic research to the different situations preceding mucosal malignancies, there is considerable evidence to propose that chronic and deep-seated abnormalities in local pH may have both a direct and an indirect role in the etiology of epithelial human cancer. A high microenvironmental pH also appears to act as a universal mediator and activating factor of many different chemical and biological carcinogens.

Undifferentiated epithelial-rich invasive malignant thymoma: complete response to cisplatin, vinblastine, and bleomycin therapy.

Two cases of complete remission plus one almost complete and another partial response of undifferentiated, invasive epithelial malignant thymoma using the combination of cisplatin, vinblastine, and bleomycin (PVB), are reported in four patients treated with this combination. Radiotherapy was instituted after completing the fourth course of chemotherapy in three patients. One patient died from intercurrent infection after the fourth cycle of combination chemotherapy. Three patients remain free of disease at the end of the treatment program. PVB appears to be highly active in this disease and deserves more extensive evaluation in multicenter clinical trials.