Abstract
Tumor hypoxia influences the outcome of treatment with radiotherapy, chemotherapy and even surgery, not only for the treatment of large bulky tumors with extensive necrosis, but also in the treatment of very small primary tumors and recurrences, micrometastases, and surgical margins with microscopic tumor involvement. Because hypoxic tumor cells are resistant to radiation and to many anticancer drugs, many approaches to circumventing the therapeutic resistance induced by hypoxia have been examined in laboratory studies and clinical trials. In this review, these approaches and the results of past laboratory and clinical studies are described and the limitations of the past agents and their testing are discussed. We describe the importance of new technologies for measuring hypoxia in human tumors, which allow assessment of pretreatment tumor oxygen levels and changes in hypoxia over the course of prolonged treatment regimens. These offer the possibility of improving the design of clinical trials and the selection of patients who will benefit from hypoxia-directed therapies, as well as the possibility of facilitating the development of better agents and regimens for use in hypoxia-directed therapy. We also discuss how the improved understanding of the abnormal vascular beds in solid tumors and of the effects of hypoxia and related microenvironmental insults, resulting from recent and ongoing research, offers the potential for finding new therapeutic targets, that may lead to the development of new agents and novel therapeutic approaches for selectively targeting cells in the adverse microenvironments within solid tumors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752413/
Hypoxia and radiation therapy: Past history, ongoing research, and future promise
Re: Hypoxia and radiation therapy: Past history, ongoing research, and future promise
Introduction
Research on the effects of hypoxia has blossomed in recent years, with the realization that hypoxia is not only an abnormal stress associated with injury and disease, but also a physiologic factor modulating a variety of normal developmental and metabolic processes. This has led to extensive studies of the many and varied molecular signaling pathways and cellular responses triggered by or modulated by moderate and severe hypoxia. This interest in and appreciation of the many effects of hypoxia has as its roots 100 years of research by radiation biologists and radiation oncologists, which was stimulated by the radiobiological effects of oxygen and by the implications of hypoxia for the treatment of cancer [1-6].
The history of research on hypoxia is intimately interwoven with the history of radiation therapy. From its earliest roots in the late nineteenth century, radiotherapy was a unique area of medicine that required the integrated use of physics, engineering, and medicine every day, in the treatment of every patient. The history of clinical and experimental radiotherapy reflects this intersection of science and medicine. Collaborations between physicians, physicists, engineers, chemists, and biologists have always been the norm in academic radiation oncology departments and professional organizations and an intrinsic part of the training and culture of the specialty [1,3-13]. Perhaps equally important in the development of radiotherapy has been the implicit assumption that the improvement of clinical care is a science that requires quantitative planning and documentation of treatments, quantitative, objective measurements of the beneficial and toxic responses to treatments, and careful evaluation of new therapeutic approaches and technologies through rigorous comparisons with the standard of care [3,5-7,9]. As noted by Béclère in 1901, “La radiotherapie ne saurent être une science sans mesures exactes” (Radiotherapy will never be a science without precise measurements) [3]. The modern concept of “evidence-based medicine” is presaged in this history.
It is probably not happenstance that the first rigorous, quantitative measurements of the survival of cells treated with cancer therapeutic agents in cell cultures [14], in tumors [15], or in normal tissues (beginning with the discovery of pluripotent bone marrow stem cells [16]) were all performed in radiobiology laboratories. Similarly, quantitative, functional endpoints for assessing injury to normal tissues and quantitative model-based analyses of tumor growth curves and of dose-response curves for tumor cure were standard models in experimental radiotherapy 50 years ago [1,5,6], when other disciplines in experimental oncology routinely used less informative endpoints such as extension of lifespan (reflecting a mixture of antitumor effects and toxicities) or ratios of the weights of treated and control tumors at a single predetermined time. Experimental and clinical studies of the therapeutic implications of tumor oxygenation therefore reflect the unique culture in the radiation oncology community, with its emphasis on close interactions between scientists and physicians, on the formulation of model-driven hypotheses, on rigorous testing of these hypotheses in laboratory studies using quantitative biological endpoints, and on clinical testing of new approaches and agents in rigorous and objective clinical trials.
As early as 1904, Hahn [17] and Schwarz [18] observed that compression that compromised blood flow changed the effects of low energy X-rays and superficial radium plaques. These observations rapidly influenced the use of these sources, although the importance of oxygen to the effects was not immediately recognized [2]. In the 1930's, Crabtree and Cramer [19] showed that molecular oxygen was a critical determinant of the response of cells to irradiation, while Mottram's histological observations of tumors in hamsters [20] led to the hypothesis that growing tumors should have areas where vascular insufficiencies caused the development of regional hypoxia.
Since these early observations, advances in science, medicine, and technology have altered radiobiology laboratories and radiation therapy clinics. This has not been a gradual, continual process; instead specific developments have suddenly and dramatically altered research and patient care. Advances in technology, including the development of high energy x-ray radiation sources and linear accelerators and improved diagnostic imaging approaches, changed radiation therapy from a palliative modality focusing on short term improvements in patient comfort into a curative modality focusing on long-term tumor control and concerned with late toxicities. This change increased the importance of developing therapies to attack radioresistant cell populations, because killing (or even inhibiting the growth of) most of the radiosensitive cells will produce good short-term palliation, but curing the tumor requires eradicating all of the malignant cells, including those which are radioresistant because of hypoxia on for other reasons. The development of inbred rodent strains, transplanted syngeneic tumor lines, and rigorous, quantitative assays to measure and compare the effects of therapies on tumors and normal tissues [1] are not ancient history: they revolutionized experimental cancer therapy during the careers of many scientists still active in the field. Similarly, the development of cell culture methodologies allowing study of well-characterized cell populations in defined media and rigorously controlled environmental conditions using quantitative clonogenic assays of cell survival [1,10,13] revolutionized studies of the effects of radiation in the 1950's and 1960's. All of these techniques were applied immediately to study the effects of oxygen and to test approaches to circumventing the radioprotective effects of hypoxia.
Attempts to use differentials in blood flow and oxygenation in tumors and normal tissues for therapeutic advantage began a century ago. They continue today. The approaches have changed as knowledge of the pathophysiology underlying tumor hypoxia has improved and as new technologies have been developed. Periods of great expectation, when major therapeutic advances were predicted to be imminent, have alternated with periods of disillusionment when these overly optimistic predictions proved false [2,4-7]. Neither extreme was probably warranted either at the time it occurred or in retrospect. In this review we will present a brief overview of past laboratory and clinical studies aimed at improving the outcome of radiotherapy by considering the implications of tumor oxygen, discuss the lessons that this history offers, and consider some ways in which recent insights into the molecular effects of hypoxia now offer new tools and technologies for use in research, new targets for therapeutic interventions and new opportunities for improving the care of cancer patients.
The bulleted topics included in the above subject .😊
Research on the effects of hypoxia has blossomed in recent years, with the realization that hypoxia is not only an abnormal stress associated with injury and disease, but also a physiologic factor modulating a variety of normal developmental and metabolic processes. This has led to extensive studies of the many and varied molecular signaling pathways and cellular responses triggered by or modulated by moderate and severe hypoxia. This interest in and appreciation of the many effects of hypoxia has as its roots 100 years of research by radiation biologists and radiation oncologists, which was stimulated by the radiobiological effects of oxygen and by the implications of hypoxia for the treatment of cancer [1-6].
The history of research on hypoxia is intimately interwoven with the history of radiation therapy. From its earliest roots in the late nineteenth century, radiotherapy was a unique area of medicine that required the integrated use of physics, engineering, and medicine every day, in the treatment of every patient. The history of clinical and experimental radiotherapy reflects this intersection of science and medicine. Collaborations between physicians, physicists, engineers, chemists, and biologists have always been the norm in academic radiation oncology departments and professional organizations and an intrinsic part of the training and culture of the specialty [1,3-13]. Perhaps equally important in the development of radiotherapy has been the implicit assumption that the improvement of clinical care is a science that requires quantitative planning and documentation of treatments, quantitative, objective measurements of the beneficial and toxic responses to treatments, and careful evaluation of new therapeutic approaches and technologies through rigorous comparisons with the standard of care [3,5-7,9]. As noted by Béclère in 1901, “La radiotherapie ne saurent être une science sans mesures exactes” (Radiotherapy will never be a science without precise measurements) [3]. The modern concept of “evidence-based medicine” is presaged in this history.
It is probably not happenstance that the first rigorous, quantitative measurements of the survival of cells treated with cancer therapeutic agents in cell cultures [14], in tumors [15], or in normal tissues (beginning with the discovery of pluripotent bone marrow stem cells [16]) were all performed in radiobiology laboratories. Similarly, quantitative, functional endpoints for assessing injury to normal tissues and quantitative model-based analyses of tumor growth curves and of dose-response curves for tumor cure were standard models in experimental radiotherapy 50 years ago [1,5,6], when other disciplines in experimental oncology routinely used less informative endpoints such as extension of lifespan (reflecting a mixture of antitumor effects and toxicities) or ratios of the weights of treated and control tumors at a single predetermined time. Experimental and clinical studies of the therapeutic implications of tumor oxygenation therefore reflect the unique culture in the radiation oncology community, with its emphasis on close interactions between scientists and physicians, on the formulation of model-driven hypotheses, on rigorous testing of these hypotheses in laboratory studies using quantitative biological endpoints, and on clinical testing of new approaches and agents in rigorous and objective clinical trials.
As early as 1904, Hahn [17] and Schwarz [18] observed that compression that compromised blood flow changed the effects of low energy X-rays and superficial radium plaques. These observations rapidly influenced the use of these sources, although the importance of oxygen to the effects was not immediately recognized [2]. In the 1930's, Crabtree and Cramer [19] showed that molecular oxygen was a critical determinant of the response of cells to irradiation, while Mottram's histological observations of tumors in hamsters [20] led to the hypothesis that growing tumors should have areas where vascular insufficiencies caused the development of regional hypoxia.
Since these early observations, advances in science, medicine, and technology have altered radiobiology laboratories and radiation therapy clinics. This has not been a gradual, continual process; instead specific developments have suddenly and dramatically altered research and patient care. Advances in technology, including the development of high energy x-ray radiation sources and linear accelerators and improved diagnostic imaging approaches, changed radiation therapy from a palliative modality focusing on short term improvements in patient comfort into a curative modality focusing on long-term tumor control and concerned with late toxicities. This change increased the importance of developing therapies to attack radioresistant cell populations, because killing (or even inhibiting the growth of) most of the radiosensitive cells will produce good short-term palliation, but curing the tumor requires eradicating all of the malignant cells, including those which are radioresistant because of hypoxia on for other reasons. The development of inbred rodent strains, transplanted syngeneic tumor lines, and rigorous, quantitative assays to measure and compare the effects of therapies on tumors and normal tissues [1] are not ancient history: they revolutionized experimental cancer therapy during the careers of many scientists still active in the field. Similarly, the development of cell culture methodologies allowing study of well-characterized cell populations in defined media and rigorously controlled environmental conditions using quantitative clonogenic assays of cell survival [1,10,13] revolutionized studies of the effects of radiation in the 1950's and 1960's. All of these techniques were applied immediately to study the effects of oxygen and to test approaches to circumventing the radioprotective effects of hypoxia.
Attempts to use differentials in blood flow and oxygenation in tumors and normal tissues for therapeutic advantage began a century ago. They continue today. The approaches have changed as knowledge of the pathophysiology underlying tumor hypoxia has improved and as new technologies have been developed. Periods of great expectation, when major therapeutic advances were predicted to be imminent, have alternated with periods of disillusionment when these overly optimistic predictions proved false [2,4-7]. Neither extreme was probably warranted either at the time it occurred or in retrospect. In this review we will present a brief overview of past laboratory and clinical studies aimed at improving the outcome of radiotherapy by considering the implications of tumor oxygen, discuss the lessons that this history offers, and consider some ways in which recent insights into the molecular effects of hypoxia now offer new tools and technologies for use in research, new targets for therapeutic interventions and new opportunities for improving the care of cancer patients.
The bulleted topics included in the above subject .😊
- Effects of oxygen on radiation response
- Approaches to Circumventing Hypoxia.
Modulating tumor oxygenation
- Oxygen-mimetic radiosensitizers
- Bioreductive Drugs and Other Hypoxic Cell Cytotoxins
- Identification and Quantification of Hypoxic Cells in Tumors
- Studies of the Tumor Vasculature
- Studies of the Physiological and Molecular Effects of Hypoxia
Last edited by D.ap on Sat Feb 01, 2020 7:57 am, edited 3 times in total.
Debbie
Re: Hypoxia and radiation therapy: Past history, ongoing research, and future promise
Conclusions
Solid tumors contain hypoxic areas from the earliest phases of their development. Tumors of the smallest sizes that are currently detectable by physical examination, diagnostic imaging, or analysis of markers such as PSA are already large enough to have initiated angiogenesis, developed regional and temporal variations in perfusion, and developed microenvironmental heterogeneity. Tumor hypoxia therefore must be considered as a factor influencing the outcome of treatment with radiotherapy, chemotherapy, and even surgery, not only for the treatment of large bulky tumors with extensive necrosis, but also for the treatment of small primary and recurrent tumors, micrometastases and surgical margins with microscopic tumor involvement. Because hypoxic tumor cells are resistant to radiation and to many anticancer drugs, many approaches to circumventing the effects of hypoxia have been examined extensively in laboratory and clinical studies. Only limited success was achieved in past studies of these approaches, but it should be remembered that improvements in local control and disease free survival seen with HBO, hypoxic cell sensitizers, and bioreductive drugs were of the same magnitude as the incremental improvements seen for adjuvant treatments with anticancer drugs that are widely regarded as therapeutic successes by the oncology community. New technologies for measuring hypoxia in human tumors and for assessing changes in hypoxia over the course of prolonged treatment regimens offer the possibility of identifying those patients who are most likely to benefit from hypoxia-directed therapies and of facilitating the development of better regimens for the use of existing hypoxia-directed agents. Agents now being tested in preclinical studies and clinical trials offer the possibility that better hypoxia-directed therapies will become available in the near future. Moreover, improved understanding of the abnormal vascular beds in solid tumors and of the effects of hypoxia and its related microenvironmental insults offer the potential for finding new targets, thereby leading to the development new agents and novel therapeutic approaches. There is therefore ample reason to believe that this century-old area of research will soon yield new therapeutic benefits.
Figure 10
Figure 10
Effect of BRCA2 deficiency on the sensitivity of cells to Mitomycin C
Solid tumors contain hypoxic areas from the earliest phases of their development. Tumors of the smallest sizes that are currently detectable by physical examination, diagnostic imaging, or analysis of markers such as PSA are already large enough to have initiated angiogenesis, developed regional and temporal variations in perfusion, and developed microenvironmental heterogeneity. Tumor hypoxia therefore must be considered as a factor influencing the outcome of treatment with radiotherapy, chemotherapy, and even surgery, not only for the treatment of large bulky tumors with extensive necrosis, but also for the treatment of small primary and recurrent tumors, micrometastases and surgical margins with microscopic tumor involvement. Because hypoxic tumor cells are resistant to radiation and to many anticancer drugs, many approaches to circumventing the effects of hypoxia have been examined extensively in laboratory and clinical studies. Only limited success was achieved in past studies of these approaches, but it should be remembered that improvements in local control and disease free survival seen with HBO, hypoxic cell sensitizers, and bioreductive drugs were of the same magnitude as the incremental improvements seen for adjuvant treatments with anticancer drugs that are widely regarded as therapeutic successes by the oncology community. New technologies for measuring hypoxia in human tumors and for assessing changes in hypoxia over the course of prolonged treatment regimens offer the possibility of identifying those patients who are most likely to benefit from hypoxia-directed therapies and of facilitating the development of better regimens for the use of existing hypoxia-directed agents. Agents now being tested in preclinical studies and clinical trials offer the possibility that better hypoxia-directed therapies will become available in the near future. Moreover, improved understanding of the abnormal vascular beds in solid tumors and of the effects of hypoxia and its related microenvironmental insults offer the potential for finding new targets, thereby leading to the development new agents and novel therapeutic approaches. There is therefore ample reason to believe that this century-old area of research will soon yield new therapeutic benefits.
Figure 10
Figure 10
Effect of BRCA2 deficiency on the sensitivity of cells to Mitomycin C
Debbie
Hypoxia-Modified Cancer Cell Metabolism
“While oxygen is critical to the continued existence of complex organisms, extreme levels of oxygen within a system, known as hypoxia (low levels of oxygen) and hyperoxia (excessive levels of oxygen), potentially promote stress within a defined biological environment. The consequences of tissue hypoxia, a result of a defective oxygen supply, vary in response to the gravity, extent and environment of the malfunction. Persistent pathological hypoxia is incompatible with normal biological functions, and as a result, multicellular organisms have been compelled to develop both organism-wide and cellular-level hypoxia solutions. Both direct, including oxidative phosphorylation down-regulation and inhibition of fatty-acid desaturation, and indirect processes, including altered hypoxia-sensitive transcription factor expression, facilitate the metabolic modifications that occur in response to hypoxia. Due to the dysfunctional vasculature associated with large areas of some cancers, sections of these tumors continue to develop in hypoxic environments. Crucial to drug development, a robust understanding of the significance of these metabolism changes will facilitate our understanding of cancer cell survival. This review defines our current knowledge base of several of the hypoxia-instigated modifications in cancer cell metabolism and exemplifies the correlation between metabolic change and its support of the hypoxic-adapted malignancy.”
https://www.frontiersin.org/articles/10 ... 00004/full
https://www.frontiersin.org/articles/10 ... 00004/full
Debbie