Biological aspects of radiation and drug-eluting stents for the prevention of restenosis

Based on recent advances, this article aims to review the biological basis for the use of either radiation or drug-eluting stents for the prevention of restenosis, and to elucidate the complementary role that they may play in the future. Vascular restenosis is a multifactorial process primarily driven by the remodeling of the arterial wall, as well as by the hyperproliferation of smooth muscle cells (SMC). These pathophysiological features are the target of therapeutic strategies aimed at inhibiting constrictive remodeling as well as inhibiting SMC proliferation. The success of radiation as well as anti-proliferative drugs such as paclitaxel and sirolimus lies in the primary and/or multifactorial inhibition of cell proliferation. Radiation has the additional feature of preventing constrictive remodeling while sirolimus has the potential property of being anti-inflammatory, which may be a desirable feature. The effects of radiation are not reliant on any uptake and "metabolism” by the target cells, as in the case with drugs, and thus radiation potentially may be more effective as a result of its more-direct action. However, radiation does have some significant drawbacks compared to drug-eluting stents, including a much delayed re-endothelialization resulting in the need for prolonged anti-platelet therapy. Based on recent clinical data, drug-eluting stents have been shown to markedly reduce the likelihood of restenosis, which actually favors this approach for the prevention of restenosis. From a biological perspective, drug-eluting stents and radiation have certain differences, which are reviewed in this articl

Oxygen Depletion in Proton Spot Scanning: A Tool for Exploring the Conditions Needed for FLASH

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-17, pub-electronic 2021-11-22Publication status: PublishedFunder: Cancer Research UK Manchester Institute; Grant(s): S_3795, C1994/A28701, 730983Funder: NIHR Manchester Biomedical Research Centre; Grant(s): BRC-1215-20007FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy

Normal tissue complications after radiation therapy Las complicaciones de la radioterapia en los tejidos sanos

This paper describes the biological mechanisms of normal tissue reactions after radiation therapy, with reference to conventional treatments, new treatments, and treatments in developing countries. It also describes biological reasons for the latency period before tissue complications arise, the relationship of dose to incidence, the effect of increasing the size of the irradiated volume, early and late tissue reactions, effects of changes in dose fractionation and dose rate, and combined chemotherapy and radiotherapy responses. Examples are given of increases in knowledge of clinical radiobiology from trials of new protocols. Potential modification to treatments include the use of biological response modifiers. The introduction of "response prediction" modifications to treatments might also be available in the near future. Finally, the paper points out that in some radiotherapy centers, the biologically-effective doses prescribed for combined brachytherapy and teletherapy treatment of cervix cancer are lower than those prescribed in other centers. This issue needs to be addressed further. The wealth of preclinical and clinical data has led to a much greater understanding of the biological basis to radiotherapy. This understanding has underpinned a variety of new approaches in radiotherapy, including both physical and biological strategies. There is also the important issue of treatment of a large number of cancers in developing countries, for which efficacious resource-sparing protocols are being continuously developed. A unified scoring system should be widely accepted as the new standard in reporting the adverse effects of radiation therapy. Likewise, late toxicity should be reported on an actuarial basis as a mandatory endpoint.En este artículo se describen los mecanismos biológicos que intervienen en las reacciones provocadas por la radioterapia, tanto con tratamientos convencionales como con los más nuevos, y los aplicados en países en desarrollo. Asimismo, se describen las bases biológicas del período de latencia que precede a la aparición de las complicaciones tisulares; la relación entre la dosis de radiación y la incidencia de complicaciones; las consecuencias de aumentar el volumen irradiado; las reacciones tisulares tempranas y tardías; los efectos de cambios en el fraccionamiento de las dosis y en las tasas de dosis; y las reacciones observadas al aplicar una combinación de quimioterapia y radioterapia. Se ofrecen ejemplos de nuevos conocimientos en el campo de la radiobiología clínica que se han adquirido mediante ensayos con nuevos protocolos. Entre las posibles modificaciones de los tratamientos figura el uso de modificadores de la respuesta biológica; en el futuro próximo, podría contarse también con modificaciones de los tratamientos para poder "predecir la respuesta". Por último, las dosis cuya eficacia biológica está demostrada y que están prescritas para tratar el cáncer cervicouterino usando una combinación de braquiterapia y teleterapia son menores en algunos centros que en otros, como se explica en este trabajo. El asunto debe examinarse más a fondo. Una gran abundancia de datos de carácter preclínico y clínico ha permitido comprender mucho mejor las bases biológicas de la radioterapia, y ello a su vez ha llevado a una serie de innovaciones en este campo, tanto en forma de estrategias físicas como biológicas. También es importante prestar atención al tratamiento de una gran variedad de cánceres en países en desarrollo, para los cuales continuamente se elaboran protocolos terapéuticos eficaces orientados a ahorrar recursos. Debería adoptarse en todas partes un único sistema de puntuación para documentar los efectos nocivos de la radioterapia. Asimismo, la toxicidad tardía debería ser un parámetro clínico de valoración obligatoria y figurar en las estadísticas de los resultados del tratamiento

Mathematical models of tissue stem and transit target cell divisions and the risk of radiation- or smoking-associated cancer

<div><p>There is compelling biological data to suggest that cancer arises from a series of mutations in single target cells, resulting in defects in cell renewal and differentiation processes which lead to malignancy. Because much mutagenic damage is expressed following cell division, more-rapidly renewing tissues could be at higher risk because of the larger number of cell replications. Cairns suggested that renewing tissues may reduce cancer risk by partitioning the dividing cell populations into lineages comprising infrequently-dividing long-lived stem cells and frequently-dividing short-lived daughter transit cells. We develop generalizations of three recent cancer-induction models that account for the joint maintenance and renewal of stem and transit cells, also competing processes of partially transformed cell proliferation and differentiation/apoptosis. We are particularly interested in using these models to separately assess the probabilities of mutation and development of cancer associated with “spontaneous” processes and with those linked to a specific environmental mutagen, specifically ionizing radiation or cigarette smoking. All three models demonstrate substantial variation in cancer risks, by at least 20 orders of magnitude, depending on the assumed number of critical mutations required for cancer, and the stem-cell and transition-cell mutation rates. However, in most cases the conditional probabilities of cancer being mutagen-induced range between 7–96%. The relative risks associated with mutagen exposure compared to background rates are also stable, ranging from 1.0–16.0. Very few cancers, generally <0.5%, arise from mutations occurring solely in stem cells rather than in a combination of stem and transit cells. However, for cancers with 2 or 3 critical mutations, a substantial proportion of cancers, in some cases 100%, have at least one mutation derived from a mutated stem cell. Little difference is made to relative risks if competing processes of proliferation and differentiation in the partially transformed stem and transit cell population are allowed for, nor is any difference made if one assumes that transit cells require an extra mutation to confer malignancy from the number required by stem cells. The probability of a cancer being mutagen-induced correlates across cancer sites with the estimated cumulative number of stem cell divisions in the associated tissue (<i>p</i><0.05), although in some cases there is sensitivity of findings to removal of high-leverage outliers and in some cases only modest variation in probability, but these issues do not affect the validity of the findings. There are no significant correlations (<i>p</i>>0.3) between lifetime cancer-site specific radiation risk and the probability of that cancer being mutagen-induced. These results do not depend on the assumed critical number of mutations leading to cancer, or on the assumed mutagen-associated mutation rate, within the generally-accepted ranges tested. However, there are borderline significant negative correlations (<i>p</i> = 0.08) between the smoking-associated mortality rate difference (current vs former smokers) and the probability of cancer being mutagen-induced. This is only the case where values of the critical number of mutations leading to cancer, <i>k</i>, is 3 or 4 and not for smaller values (1 or 2), but does not strongly depend on the assumed mutagen-associated mutation rate.</p></div

Probabilities of cancer for various sites, conditional probability of a cancer being mutagen induced (expression (9)), and the relative risk (expression (10)), assuming a spontaneous mutation rate (<i>u</i>_<i>S</i>) = 10⁻⁸ per cell division, and <i>k</i> = 2 to 4 critical cancer genes, mutagen-associated rates increase from 0 after the first third of stem cell divisions, using a generalization of the model of Wu <i>et al</i>. [11].

<p>Assumptions as to the number of symmetric (<i>n</i>₁) and asymmetric cell divisions (<i>n</i>₂) are as for the paper of Wu <i>et al</i>. [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005391#pcbi.1005391.ref011" target="_blank">11</a>].</p

Schematic diagram of generalized cancer model with <i>k</i> mutations, allowing for mutations in stem cell and transit cell compartments.

<p>This is a special case of the fully-stochastic destabilization model developed by Little <i>et al</i>. [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005391#pcbi.1005391.ref013" target="_blank">13</a>].</p