Thesis (Ph.D.)--Stellenbosch University, 2000. / ENGLISH ABSTRACT:
Predictive assays are of key importance in clinical radiotherapy, chemotherapy
and toxicology. Prior to exposing malignant tissues to irradiation or drugs in
the clinic, a good understanding of the damage response to the cytotoxic agent
is required. Such information is necessary for effective planning and treatment.
Regrettably however the methods which detect DNA damage, namely
micronucleus, apoptosis and DNA repair assays do not rank cells according to
their intrinsic survival response to cytotoxic agents. The application of
predictive assays based on micronuclei and apoptosis in the clinic therefore
remains unreliable. Using a panel of 7 neuroblastoma and 6 neuroepithelial
cell lines, it is shown that damage assays also do not rank cell lines according
to cell survival. However, radiosensitivity can be reconstructed from
micronuclei formation and apoptosis, and a new parameter, cell death due to
small deletions, chromosome aberrations and misrepair. The interrelationships
between radiation-induced micronuclei, apoptosis and repair is complex and
varies between cell lines. Micronuclei formation and apoptosis are
exponentially interrelated. This suggests that these cell inactivation pathways
are strongly correlated. Evidence exists to show that the expression of
apoptosis and micronuclei is influenced by the extent of DNA double-strand
break repair within the first 2 hours after irradiation. Cell lines which repair
more damage in the first 2 hours express more micronuclei and less apoptosis.
Micronuclei formation and apoptosis and are not significantly correlated with
the 20 hours slow repair component. There is however a strong correlation between 20 hours of repair and radiosensitivity, with the more radioresistant
cell lines being more repair proficient. This suggests that the 2 hours (fast)
DNA repair component is more error prone, and that cells lines repairing more
damage late after irradiation tend to show better survival. In conclusion,
micronuclei formation, apoptosis and DNA repair are strictly cell type specific
and are not suitable for predicting radiosensitivity in terms of cell survival.
However, these assays are very useful for studies on the influences of dose
modifying agents i.e. oxygen tension, radiation modality, pH, cytotoxic
sensitisers and radiation protectors which alter cellular responses and provide
insight into damage mechanisms. / AFRIKAANSE OPSOMMING: Toetse wat kliniese gevolge kan voorspel is van uiterse beking in
stralingsterapie, chemoterapie en toksikologie. Voordat kwaadaardige
weefsels aan bestraling of chemise middels blootgestel can word in die kliniek,
moet daar 'n goeie begrip van die skade weerstand wees van die selgiftige
middel. Hierdie inligting is noodsaaklik vir effektiewe beplanning en
behandeling. Ongelukkig stem die metodes wat ONS skade, apoptose en
ONS hersteltoetse, nie ooreen met die selle se inherente straling sensitiwiteit
nie. Die aanwending van voorspelbare toetse gebaseer op mikrokerne en
apoptose in die kliniek bly dus onbetroubaar. Deur gebruik te maak van 'n
paneel van 13 neurologiese sellyne, is daar bewys dat ONS skade toetse nie
sellyne rangskik volgens seloorlewing nie. Radiosensitiwiteit kan herbou word
deur 'n neiging om mikrokerne te vorm, apoptose, en sel sterftes weens klein
vermiste ONS volgordes, chromosoom aberrasies en verkeerd herstelde ONS.
Die verhouding tussen straling-geïnduseerde mikrokerne, apoptose en selgenees
is kompleks en varieer tussen sellyne. Die ontstaan van mikrokerne
en apoptose is eksponensiel verbind. Dit dui aan dat hierdie
seltraagheidsbane streng gekorreleer word. Daar is bewys dat die uitdrukking
van apoptose en mikrokerne deur die mate van herstel van die ONS
dubbelstring-breuke binne die eerste 2 ure na bestraling beïnvloed is. Daar is
gevind dat sellyne wat meer skade herstel binne die eerste 2 ure meer
mikrokerne en minder apoptose toon. Die ontstaan van mikrokerne en apoptose is nie betekenisvol gekorreleer met die 20-uur stadige herstel
komponent nie. Daar is inderdaad 'n sterk korrelasie tussen die 20-uur herstel
komponent en radiosensitiwiteit, en die meer radioweerstandbiedende sellyne
net In hoër herstel bekwaamheid. Dit laat mens dink dat die 2 uur (vinnige)
DNS herstel komponent meer geneig is om foutief te wees, en dat sellyne wat
meer skade, laat na bestraling herstel, beter oorlewing toon. Ten slotte, die
ontstaan van mikrokerne, apoptose en DNS herstel is strenggesproke seltipe
spesifiek en is nie toepaslik om radiosensitiviteit, in terme van seloorlewing, te
voorspel nie. Hierdie toetse is nuttig vir studies waar die invloed van
dosismodifiseringsagente, soos suurstof-spanning, straling-tipe, pH,
sitotoksieke sensiteerders en stralingsbeskermers, wat sellulêre gevoeligheid
verander en insig gee tot skade meganismes.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/51755 |
| Date | 12 1900 |
| Creators | Akudugu, John Mbabuni |
| Contributors | Böhm, E. L. J. F., Slabbert, J. P., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiation Oncology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | 162 p. : ill. |
| Rights | Stellenbosch University |
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