550 / 1082
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ESTRO 36 2017
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cm) with 10Gy single fraction prescribed to the 70%
isodose line (Dmax 14 Gy). No patient got
chemotherapy/immune therapy.
Results
10Gy- in vitro induced abscopal effect in hypoxic
conditions was very effective in inducing growth delay of
both, unirradiated normoxic and hypoxic lung cancer cells
(Table 1), so we moved forward with clinical application
of bystander/abscopal effect. In all the treated patients,
a significant bystander effect after mean time of 3 weeks
and in 1 of the patients significant abscopal effect was
also observed (Figure 2). Overall response rates for
symptom relief and mass response were 100% (1 complete
and 4 good partial response).No patient experienced acute
or late toxicity of any grade.
Conclusion
Considering
the clinical benefit/toxicity ratio, the clinical
exploitation
of
biological
properties
of
bystander/abscopal effect induced by partial irradiation
of large tumor masses, and almost any dose distribution to
the normal tissue outside the irradiated tumor, could
make bystander/abscopal effect at least more effective
than conventional radiation therapy for treatment of
advanced cancers and the perfect treatment option for
symptomatic patient. Further, by inducing the distal
responses, like in the case of one of the patients,
'radiation/hypoxia induced abscopal effects” offer one
more possibility for the oligometastatic population also to
get cured. We continue to investigate this hypothesis in
the laboratory and clinical setting.
Poster: Radiobiology track: Radiobiology of colorectal
cancer
PO-0976 Mechanisms of normal tissue t oxicity from
SAHA, an HDAC inhibitor and radiosens itizer
I.S. Barua
1,2
, A.H. Ree
1,2
, L. Sønstevold
1
, K.R . Redalen
1
,
E. Kala nxhi
1
1
Akershus University Hospital- Norway, Dep artment of
Oncology, Oslo, Norway
2
Institute of Clinical Medicine- University of Oslo,
Campus AHUS, Oslo, Norway
Purpose or Objective
Histone deacetylase inhibitors (HDACi) are therapeutic
agents, which through epigenetic alterations can cause
tumor cell death and have shown radiosensitizing
properties in preclinical models. HDACi have been largely
regarded as tumor-specific, while their effects on normal
tissues remain poorly investigated. The latter is important
as an increase in therapeutic efficacy resulting from
combining such agents with radiotherapy may come at the
expense of patient tolerance, undesired treatment
interruptions and dose limitations. In the phase I Pelvic
Radiation and Vorinostat (PRAVO) study, we investigated
mechanisms of adverse effects to the HDACi vorinostat
(suberoylanilide hydroxamic acid; SAHA) when given as
potential
radiosensitizer.
Vorinostat-induced
transcriptional responses in patients’ peripheral blood
mononuclear cells implicated cell death pathways as a
possible mechanism of toxicity. In experimental models
we showed that apoptosis in epithelial cells of the
intestinal mucosa may account for the gastrointestinal-
related adverse effects commonly associated with the use
of HDACi (Kalanxhi E, et al. Cancer Res Treat, 2016). In
the current work we further investigate HDACi-induced
apoptosis and the possible interplay with autophagy in
experimental normal and colorectal cancer (CRC) models.
Material and Methods
Two normal cell lines (rat IEC-6 intestinal epithelial cells,
human BJ fibroblasts) and two CRC cell lines (HCT116,
HT29) were exposed to a therapeutically relevant
concentration of SAHA alone, or in combination with the
caspase inhibitor ZVAD-fmk and the autophagy inhibitor
bafilomycin A1 for 24 hours. Induction of apoptosis and
autophagy were analyzed with flow cytometry (Annexin
V/PI staining) and western blot analysis (LC3 I/II and p62
expression).
Results
SAHA induced apoptosis in the CRC cell lines with 42% and
26% of the HCT116 and HT29 cell populations respectively,
showing Annexin V/PI staining indicative of early and late
phases of apoptosis (Figure 1). Normal BJ fibroblasts
remained unaffected, whereas intriguingly, intestinal
epithelial IEC-6 cells responded similarly as the cancer
cells, although apoptosis was induced at a lesser extent
(18% of cells). Addition of ZVAD-fmk halved the number of
apoptotic cells in CRC cells, whereas the same number of
IEC-6 cells (16%) displayed apoptotic phenotypes. We
further looked into induction of autophagy and found that
SAHA induced autophagy both in the CRC cell lines and the
IEC-6 cells, as reflected by increased levels of the