Evaluation of the effect of radiofrequency electromagnetic waves on radiosensitivity

Chinhengo, Angela (2019-12)

Thesis (PhD)--Stellenbosch University, 2019.

Thesis

ENGLISH SUMMARY : Cancer is a major cause of human death worldwide, and one of the very real challenges is how to control treatment resistance. An additional challenge is the co-morbidity of cancer, with certain infections complicating its management. Radiotherapy (RT) is considered the first line of treatment for most superficial cancers, as these malignancies tend to respond well to radiation. The use of hypofractionated treatment may be beneficial for certain tumours, but hypofractionation may result in severe side-effects from normal tissue toxicity from which the patient may not recover. To circumvent this, radiation modifying agents that potentiate the tumour inactivating effects of ionising radiation and thereby lead to a reduction in radiation dose and prevent normal tissue toxicity, can be utilised. Magnetic fields have long been suggested as potential enhancers of radiation effects. Studies on the combined biological effects of radiofrequency fields (RFF) and ionising radiation are virtually non-existent. The use of RFF adjuvant to radiotherapy may be beneficial, as they have been shown to exhibit in vitro radiosensitising and radioprotective effects in malignant and normal cells, respectively, with the possibility of a significant dose reduction. There is, however, a need to understand the mechanisms by which these RFF influence radiosensitivity so that they can be employed efficiently as radiotherapy modulators. The main goal of radiotherapy is to kill tumour cells and spare normal tissue, and a good modifying agent would be one that sensitises the tumour whilst protecting normal tissue. This study assessed the effect of radiofrequency fields (RFF), modulated at 100, 1000, 2000 and 4000 Hz, on the radiosensitivity of four cell lines: a p53 mutant melanoma cell line, MeWo; a p53 wild-type melanoma cell line, Be11; a p53 mutant prostate cancer cell line, DU145; and a p53 wild-type normal lung fibroblast cell line, L132. The radiomodulatory effect of radiofrequency fields was evaluated using the colony assay. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), superoxide dismutase (SOD) and micronucleus assays were used to assess the possible mechanisms by which radiofrequency fields influence the radiosensitivity of cells. The data demonstrate that radiofrequency fields are more efficient in modulating large fractional doses of X-rays and could find application in hypofractionated radiotherapy as adjuvants, especially for tumours with low alpha/beta ratios. This can have a positive impact on the management of patients with superficial tumours that may be resistant to low fractional doses of radiation. Radiofrequency fields modulate cellular radiosensitivity in a frequency- and cell type-dependent manner and their effects appear to be linked to p53 status. Cellular responses such as metabolism, DNA damage processing (based on micronuclei formation), and abnormal proliferation (based on binucleation) seem to be underlying factors mediating the radiomodulatory effects of radiofrequency fields. Mechanisms by which radiofrequency fields can possibly modulate radiosensitivity are: amplification of radiation-induced genotoxicity, cell cycle arrest, and disturbance of other cellular biochemical processes that lead to alteration of homeostasis. Alternative ways by which RFF affect radiosensitivity are: interfering with the synthesis and function of charged proteins in the cell leading to programmed cell death or premature cell ageing, perturbation of intracellular calcium ions which can trigger apoptotic or necrotic cell death, and/or modulating the expression of Bcl-2 family proteins. Given this complexity, a potential use of radiofrequency fields as a non-invasive therapeutic modality would require standardisation to establish reproducibility. A more detailed understanding of how radiofrequency fields interact with ionising radiation would also prove beneficial in the broader field of radiation protection.

AFRIKAANSE OPSOMMING : Kanker is wêreldwyd ‘n belangrike oorsaak van die dood in mense, en een van die werklike uitdagings is hoe om weerstand teen behandeling te voorkom. ‘n Addisionele uitdaging is dat die komorbiditeit van kanker en infeksies die behandeling bemoeilik. Bestralingsterapie word by voorkeur as die eerste keuse van behandeling vir die meeste van die oppervlakkige kankers beskou, want hierdie kwaadaardige siektes is kwesbaar vir bestraling. Die gebruik van hipofraksioneerde behandeling mag voordelig vir die behandeling van sekere tumore wees, maar hipofraksionering mag moontlik bykomstige nadelige gevolge in die vorm van onomkeerbare lewensbedreigende toksisiteit inhou. Om dit te voorkom, kan stralingsmodifiërende strategieë gebruik word, met die vermoë om die tumorinaktivering te potensieer, bestralingsdosis te verlaag en weefseltoksisiteit van normale weefsel te verminder. Magnetiese velde word lankal as ‘n potensiële versterker van stralingseffekte beskou. Studies oor die gekombineerde biologiese uitwerking van radiofrekwensievelde (RFV) en gëioniseerde bestraling is selde gerapporteer. Die benutting van radiofrekwensievelde saam met bestraling mag voordelig wees, want dit is bewys dat hierdie kombinasieterapie in vitro daarin slaag om maligne en normale selle teen bestralingskade te beskerm, omdat die bestralingsdosis aansienlik verlaag kan word. Dit is egter nodig dat die meganismes, waardeur radiofrekwensievelde die bestralingsensitiwiteit beїnvloed, opgeklaar word sodat dit voordelig as modulators van radioterapie aangewend kan word. Die hoofdoel van radioterapie is om tumorselle dood te maak en om normale selle te beskerm. ‘n Nuttige modulator is dié wat normale selle beskerm, terwyl dit tumorselle kwesbaar maak. Hierdie studie het die effek van radiofrekwensievelde (RFV) gemoduleerd met 100, 1000, 2000, en 4000 Hz, op die verhouding van die radiosensitiwiteit van vier sellyne evalueer: ‘n p53-mutant melanoomsellyn, MeWo; ‘n p53-wildetipe melanoomsellyn, Be11; ‘n p53-mutant prostaatkankersellyn, DU145; en ‘n p53-wildetipe normale long-sellyn, L132. Die stralingsregulerende effek van radiofrekwensievelde is bereken deur die gebruik van kolonie-essaiëring. Die MTT, SOD en mikrokerntoetse is gebruik om die moontlike meganismes waardeur radiofrekwensievelde die radiosensitiwiteit van selle beїnvloed, te bepaal. Die data bewys dat radiofrekwensievelde meer doeltreffend is wanneer dit toegepas word op modulering van groot gefraksioneerde dosisse X-strale en mag dien as bykomende hipofraksioneerde stralingsterapie, veral in tumore met lae alfa/beta-verhoudings. Hierdie addisionele voordeel kan verder benut word by die behandeling van pasiënte met oppervlakkige tumore wat weerstandig is teen lae gefraksioneerde stralingsdosisse. Radiofrekwensievelde moduleer die radiosensitiwiteit van selle op ‘n frekwensie- en seltipe-afhanklike wyse en die uitwerking blyk gekoppel te wees aan p53-status. Sellulêre reaksies soos metabolisme, DNS-skadeprosessering (gebaseer op mikrokernvorming), en abnormale proliferasie (gebaseer op dubbelkernvorming) skyn onderliggende faktore te wees wat die radiomodulerende effekte van radiofrekwensievelde medieer. Meganismes waardeur radiofrekwensievelde moontlik die radiosensitiwiteit kan reguleer, is: versterking van bestralingsgeїnduseerde geentoksisiteit, selsiklusarres, en versteuring van ander sellulêre biochemiese prosesse wat lei tot versteuring van homeostase. Alternatiewe meganismes waardeur RFV radiosensitiwiteit bëinvloed, is: versteuring van die sintese en funksionering van intrasellulêre polêre proteїene wat lei tot geprogrammeerde seldood of premature veroudering van selle, ontwrigting van intrasellulêre kalsiumioonekwilibrium wat apoptose of nekrotiese seldood kan sneller en/of die uitdrukking van Bcl-2- familieproteїene kan moduleer. Teen die agtergrond van hierdie ingewikkelde oorwegings, verg die potensiële benutting van radiofrekwensievelde as ‘n nie-indringende terapeutiese modulator standaardisasie om herhaalbaarheid vas te stel. ‘n Meer gedetailleerde begrip van hoe presies die interaksie van radiofrekwensievelde met geїoniseerde bestraling verklaar kan word, mag ook van toepassing wees op die gebied van beskerming teen bestraling op velerlei ander gebiede.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/107194
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