Wirkung von Protonen auf HPV neg. und pos. HNSCC-Zellen und die gezielte Verstärkung durch PARP-Inhibition
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Abstract
Squamous cell carcinoma of the head and neck (HNSCC) are among the ten most
frequent cancer worldwide. A distinction is made between HPV neg. and pos. HNSCC,
which are either associated with tobacco consumption or alcohol abuse or which are
induced by human papillomavirus (HPV).
Treatment of HNSCC by Cisplatin-based radio-chemotherapy results in a rather good
response for HPV pos. HNSCC with an overall survival of 80%, in contrast to only 50%
for HPV neg. HNSCC. However, the therapy is often associated with severe side effects
strongly reducing the quality of life. There is a chance that the therapy of these patients
may be improved when using proton irradiation especially because of less side effects.
The aim of this study was to clarify, whether similar as seen for photons also for
protons a higher effect is achieved for HPV pos. HNSCC cells. It was additionally tested
whether the effect of protons can be enhanced by the inhibition of PARP. The
experiments were performed with five HPV neg. (UMSCC-3, UMSCC-6, UMSCC-11b,
UTSCC-33, FaDu) and five HPV pos. (UDSCC-2, UMSCC-47, UMSCC-104, 93VU-
147T, UPCI:SCC-154) cell lines. For the inhibition of PARP the two recent drugs Olaparib
and Talazoparib were used. Radiosensitivity was determined by colony forming assay,
DNA replication stress and double-strand break repair by 53BP1/CenpF co-staining.
The following results were obtained:
1. For photon irradiation the significant higher radiosensitivity of HPV pos. cells
was confirmed.
2. Also, for protons a significantly higher radiosensitivity was seen for HPV pos.
cells.
3. The relative biological effectiveness (RBE10) was slightly higher for HPV neg.
cell lines with RBE10=1.14±0.04 when compared to RBE10=1.01±0.01 for HPV
pos. cell lines.
4. Inhibition of PARP by Olaparib had no effect on cell survival, while a strong
cytotoxicity was seen when using Talazoparib. Surprisingly this effect was
much stronger for the HPV neg. cell line UMSCC-6 with PE=30% in contrast
to PE=70% for the HPV pos. cell line UPCI:SCC-154.
5. For HPV neg. cells Talazoparib also led to a drastic DNA replication stress
(RS). This was evident by the great number of S-phase cells with dispersed
53BP1 foci and which was associated with a strong block in this phase. Clearly
less RS was seen for HPV neg. cells when treated by Olaparib. No such effects
were detected for HPV pos. cells.
6. Both inhibitors led to an increase in radiosensitivity, whereby this effect was
higher for Talazoparib. These effects, however, were much stronger for the
HPV pos. cell line when compared to the HPV neg. cell line.
Overall, these data demonstrate, that therapy by protons is an optimal alternative to
the conventional photon therapy. Effect of protons can even be enhanced by PARP
inhibition especially for HPV pos. HNSCC. In this respect Olaparib appears to be better
candidate, because of the high cellular toxicity caused by Talazoparib.
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