Die Wirkung von Kohlenstoffionenbestrahlung auf die Überlebensrate und Doppelstrangbruchreparatur von HPV-positiven und -negativen HNSCC-Zellen

Plattenepithelkarzinome der Kopf-Hals-Region (HNSCC) sind mit über 600.000 Neuerkrankungen pro Jahr die sechsthäufigste Tumorerkrankung weltweit. Sie lassen sich ätiologisch in eine primär noxen-bedingte (HPV-negative) Gruppe und eine mit Hoch-Risiko-Typen des Humanen Papilloma-Virus assoziierte (HP...

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Bibliographic Details
Main Author: Lerch, Stefan
Contributors: Engenhart-Cabillic, Rita ( Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2023
Subjects:
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Tumors of the head and neck region (HNSCC) are the sixth most common cancer worldwide with nearly 600.000 new cases every year. They can be subdivided in a subgroup which is mainly driven by noxa (HPV-negative) and a subgroup which is mainly depending on a chronic infection with a high-risk pamilloma virus (HPV-positive). In advanced stages these tumors are generally treated by photon-based radiochemotherapy. It is shown in several studies that patients with HPV-positive HNSCC profit more from the therapy than patients with HPV-negative HNSCC. This is considered to result from an increased cellular radiosensitivity of HPV-positive HNSCC caused by a defect in DNA double strand break repair. This stronger effect leads to an increased 5-year overall survival rate (>80%) of patients with a p16-positive tumor which is a surrogate marker for HPV positivity and therefore also a prognostic marker. The 5- year overall survival of patients with HPV-negative HNSCC is worse with about 50% mainly depending on the state. Therefore, a therapy escalation is necessary to increase the survival rates of patients with HNSCC. However, even the therapy schemes which are currently used are accompanied with substantial rates of side effects like mucositis, xerostomia or dysphagia. This leads to a relevant number of cases which need artificial feeding or makes it even necessary to break up the therapy. For HNSCC a promising alternative is seen in the high conformal irradiation with carbon ions (12C-ions). This radiation quality allows a strong local effect on the tumor with a noticeable protection of the normal tissue at the same time. Before starting a clinical trial with 12C-ion irradiation on patients the effects of these ions on HNSCC cells must be known. The aim of this study was to obtain these data by using five HPV-negative and five HPV-positive HNSCC cell lines. The following results were obtained: • The study could confirm the higher radiosensitivity of HPV-positive HNSCC cells for irradiation with photons. • The irradiation with 12C-ions leads to an increase of radiosensitivity in HPV- positive and HPV-negative HNSCC cells. • 12C-ion irradiation showed a lower relative biological effect on HPV-positive HNSCC cells than on HPV-negative HNSCC cells. • The difference in the relative biological effectiveness led to an alignment of cellular survival of HPV-positive and HPV-negative HNSCC cells after 12C-ion irradiation. • More residual DNA double strand breaks can be found in HPV-positive cells than in HPV-negative cells after photon irradiation. After 12C-ion irradiation there was no significant difference. • The association between residual DNA double strand breaks and cell survival shows that both after photon irradiation and after 12C-ion irradiation cellular survival is mainly depending on the DNA double strand break repair efficacy. It is shown here for the first time that the cellular survival of HPV-positive and HPV- negative HNSCC cells does not differs significantly after an irradiation with 12C-ions. This stands in contrast to the huge difference previously found after photon irradiation. This marked difference needs to be considered when planning new trials for the clinical application of 12C-ion irradiation for patients with both HPV-negative and HPV-positive HNSCC. Parts of this work were published: Lerch, S., Berthold, S., Ziemann, F., Dreffke, K., Subtil, F.S.B., Senger, Y., Jensen, A., Engenhart-Cabillic, R., Dikomey, E., Wittig, A., Eberle, F., Schötz, U., 2020. HPV-positive HNSCC cell lines show strongly enhanced radiosensitivity after photon but not after carbon ion irradiation. Radiother. Oncol. 151, 134–140.