Jorritsma, Jozef Bonifacius Maria

English

The many studies undertaken recently have increased the possibilities to use hyperthermia in cancer treatment. Heat treatment of tumours, which is usually at temperatures between 40 and 46 ˚C, has two effects which are advantageous for cure. Cells appear to lose their clonogenic ability by the heat treatment itself (hyperthermic cell killing). Moreover, the cells surviving the heat treatment show an enhanced cell killing, when treated with radiation (hyperthermic radiosensitization). Both effects usually increase with treatment time and temperature. The combined heat and radiation treatment especially offers new potentials in cancer therapy. Not only in those cases where low radiation doses are prescribed, but as well because often radioresistant tumour cells will be hypersensitive to heat (see 1.1. and 8.7). ... ZieL Summar

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   University of GroningenHyperthermic cell killing and radiosensitization. Role of DNA repair.Jorritsma, Jozef Bonifacius MariaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1986Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Jorritsma, J. B. M. (1986). Hyperthermic cell killing and radiosensitization. Role of DNA repair. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-06-2022SummaryThe many studies undertaken recently have increased the possibilities to usehyperthermia in cancer treatment. Heat treatment of tumours, which is usually attemperatures between 40 and 46oC, has two effects which are advantageous for cure.Cells appear to lose their clonogenic ability by the heat treatment itself (hyperthermiccell killing). Moreover, the cells surviving the heat treatment show an enhanced cellkilling, when treated with radiation (hyperthermic radiosensitization). Both effectsusually increase with treatment time and temperature. The combined heat andradiation treatment especially offers new potentials in cancer therapy. Not only inthose cases where low radiation doses are prescribed, but as well because oftenradioresistant tumour cells wil l be hypersensitive to heat (see 1.1. and 8.7.).Both from a scientif ic point of view, as well as in order to optimize the applicationof hyperthermia, it is important to know the mechanisms underlying hyperthermic cellki l i lng and radiosensitization. As radiation-induced cell death is probably caused byunrepaired DNA damage (see 1.2.), the experimental work described in this thesis isdirected towards the effect of hyperthermia on DNA repair. Suspension culturedmurine Ehrlich Ascites Tumour cells (EAT) and HeLa Sr human cervical carcinomacells were used for the experiments. The results were more or less identical for both celll ines.Hyperthermia inhibits the rate of repair of DNA strand breaks, an ubiquitouslyoccurring type of DNA damage after radiation (chapter 2) and reduces the activity ofDNA polymerases, which are known to be involved in DNA repair (chapter 5).Modification of the heat treatment was used as a tool to study the relationship betweenstrand break repair and DNA polymerase activity on one hand, and hyperthermic cellkilling and radiosensitization on the other. The cell-killing effect of hyperthermia canbe reduced by the addition of erythritol during the heat treatment or by the inductionof thermotolerance by repeated heat treatments. Cell ki l l ing can be enhanced byaddition of procaine during hyperthermia or by "step-down" heating (thermo-sensitization). The extent of hyperthermic cell killing, radiosensitization, inhibition ofDNA polymerase activity, and the rate of strand-break repair were compared underthe different circumstances.The hyperthermic inhibition of strand-break repair was influenced qualitatively aswell as quantitatively by procaine, erythritol (chapter 4) and thermotolerance (chapter6) in the same way as observed for hyperthermic cell killing.A small number of DNA strand breaks was observed to arise from hyperthermiaalone (chapter 3). As the number of these strand breaks was not influenced by thepresence of procaine, erythritol or thermotolerance, this type of DNA lesion could notdirectly be related to hyperthermic cell killing. These strand breaks are more probablycaused by alterations in the nuclear skeleton (see below), for example as a result oftorsion of the adhered chromatin. Further investigations into the formation and repairof these breaks after lower heat doses and their cell cycle dependency are necessarybefore definite conclusions can be drawn (chapter 8).DNA polymerase activity (especially polymerase p activity) was influenced in thesame was as cell killing by the presence of procaine or erythritol during the heattreatment (chapter 5). These agents act indirectly, probably at the level of the plasmamembrane, as the effects were only observed in the case of intact cells and not whent46isolated nuclei were used (chaptcr 5). The lack of an effect of thermotolerance orthermosensitization at the level of hyperthermic DNA polymerase inactivation(chapter 5,6,7), shows that the inhibit ion of polymerase activity can neither expiainhyperthermic cell ki l l ing nor the hyperthermic inhibit ion of strand-break repair.Likewise, the extent of hyperthermic radiosensitization was uninfluenced bythermotolerance or thermosensitizalion (chapter 6,7). Therefore, hyperthermicradiosensitization appears to be unrelated to the inhibit ion of strand-break repair,which was influenced by thermotolerance. A high correlation coefficient was foundfor the relationship between radiosensitivity and the extent of polymerase inactivationin thermotolerant cells (chapter 6). After thermosensitization this value was lowerthan expected, however, which implicates that the reduced polymerase activity cannotfully explain hyperthermic radiosensitization either.Alterations in nuclear structure after hyperthermia are expressed as an enhancedprotein content and a reduced sedimentation of nuclei isolated from heated cells(chapter 5). Other reports in the l iterature indicate that these alterations are attendedwith a reduced accessibil i ty of the DNA for repair enzymes.In conclusion the results show that DNA repair is inhibited by hyperthermia throughmembrane damage, inactivation of repair enzymes, as well as alterations in chromatinstructure. The inhibit ion of the DNA repair capacity is the most l ikely cause ofhyperthermic radiosensitization. The parameters investigated, strand-break repaircapacity and DNA polymerase activity, do not appear to be the rate l imiting stepunder all circumstances. Above all, the alteration in chroniatin structure has to beinvestigated into more detail. A reduced DNA repair capacity of naturally occurringor hyperthermia-induced DNA damage, may as well be the cause of cell ki l l ing by heata lone.t47

Hyperthermic cell killing and radiosensitization. Role of DNA repair.

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Hyperthermic cell killing and radiosensitization. Role of DNA repair.

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