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countries now have paedidatric stratified medicine
programmes underway or in development, and the first
multi-arm, multi-Pharma company European paediatric
basket trial – e-SMART – is due to open for relapsed and
refractory tumours. At a strategic level, consultation is
underway for the EU ‘Paediatric Regulation’ which it is
hoped will further increase access of children to novel
therapies by removing the facility for Pharma companies
to apply for waivers for paediatric testing. In an era of
molecularly driven therapy, such waivers have no logical
basis in the majority of cases.
OC-0591 Hypoxic cell killing by SN36506, a novel
hypoxia-activated prodrug
R. Niemans
1
, A. Yaromina
1
, J. Theys
1
, A. Ashoorzadeh
2
,
R. Anderson
2
, M. Bull
2
, C. Guise
2
, H.L. Hsu
2
, M.
Abbattista
2
, A. Mowday
2
, A.V. Patterson
2
, J.B. Smaill
2
, L.
Dubois
1
, P. Lambin
1
1
Maastricht Radiation Oncology MAASTRO GROW - School
for Oncology and Developmental Biology- University
Maastricht, Department of Radiotherapy, Maastricht,
The Netherlands
2
University of Auckland, Auckland Cancer Society
Research Centre, Auckland, New Zealand
Purpose or Objective
Hypoxia is a common feature of solid tumors. Conventional
treatments such as chemo- and radiotherapy (RT) are less
effective against hypoxic tumor cells. Hypoxia-activated
prodrugs (HAPs) are specifically activated under hypoxic
conditions to directly target these as well as adjacent
more oxygenated tumor cells via their bystander effect.
SN36506 is a newly developed nitroaromatic HAP with
highly favorable properties: 1) activation under hypoxia,
2) high bystander effect, 3) excellent aqueous solubility,
4) murine oral bioavailability and 5) no off-mechanism
activation by human aerobic reductases. Here we tested
the cytotoxic effects of SN36506
in vitro
and
in vivo
.
Material and Methods
IC
50
viability ratios were assessed in 2D cell culture
exposed to normoxic or anoxic (≤0.02% O
2
) conditions in a
panel of human tumor cell lines. H460 lung tumor
multicellular layers (MCLs) were incubated with SN36506
under aerobic (5% CO
2
, 95% O
2
) or anoxic (5% CO
2
, 95% N
2
)
conditions and plated for clonogenic cell survival (CCS). In
addition, H460 spheroids were incubated with SN36506,
after which single cell suspensions were made and cells
were plated for CCS.
Mice bearing H460 xenografts received a single i.p. dose
of SN36506 (781 mg/kg) after irradiation (10 Gy) of
tumors. 18 h later tumors were excised, single cell
suspensions were prepared and plated for CCS.
Mice bearing xenografts of a range of tumor cell lines
received one i.p. dose of SN36506 (800 mg/kg) per day on
5 consecutive days (QD5). Treatment started when tumors
reached a volume of approximately 200 mm
3
, and tumor
volumes were followed-up after treatment.
Results
IC
50
were lower in anoxia than normoxia by factors of 20.17
(SiHa), 55.11 (C33A), >7.84 (HCT116), >3.66 (DLD-1),
>12.9 (MDA-MB-468), >2.67 (H1299) and >6.21 (H460). In a
H460 MCL clonogenic assay, 100 µM SN36506 caused 99%
cell kill under anoxia but exhibited no aerobic cell kill.
SN36506 caused a concentration-dependent decrease in
survival of clonogens derived from hypoxic spheroids but
had no effect on clonogenic cells from non-hypoxic
spheroids, indicating hypoxia-specific cell kill. A single
dose of SN36506 significantly reduced clonogenic cell
survival when combined with RT in an
in vivo
excision
assay (log cell kill 2.35 relative to control). Furthermore,
in vivo
800 mg/kg QD5 of SN36506 caused xenograft
growth inhibition of 99.6% (MDA-MB-468), 81% (A2780),
52% (H460) and 41% (SiHa).
Conclusion
In vitro
, SN36506 preferentially kills tumor cells in hy
poxic conditions and reduces clonogenic cell survival of
hypoxic spheroids only.
In vivo,
SN36506 sterilizes
radiation resistant hypoxic tumor cells, and strongly
inhibits tumor growth. As such, SN36506 is a promising
new HAP with potentially favorable properties for clinical
use. Further studies to determine the antitumor effects of
SN36506 as a monotherapy and in combination with RT in
several preclinical tumor models are ongoing.
Symposium: Applications and challenges in dosimetry
for MR-linacs
SP-0592 Reference dosimetry: getting the basics and
calibration right
S. Duane
1
National Physical Laboratory, Teddington, the United
Kingdom
Abstract not received
SP-0593 Clinical commissioning of MR guided treatment
systems
O. Green
1
Sietman Cancer Center, Saint Louis, USA
Abstract not received
SP-0594 Pre-treatment phantom dosimetry: effects in
different phantoms and detectors
B. Van Asselen
1
, J.W.H. Wolthaus
1
, S.L. Hackett
1
, J.G.M.
Kok
1
, S.J. Woodings
1
, B.W. Raaymakers
1
1
UMC Utrecht, Department of Radiation Oncology,
Utrecht, The Netherlands
The excellent visualization of soft-tissue with MRI can
allow direct visualization of the tumor when applied
during the delivery of radiotherapy. Several designs,
which combine MRI with either an accelerator or Co-60,
are being developed or in clinical use. At the UMC Utrecht
a clinical prototype is installed which integrates a 1.5 T
MRI scanner and a 7 MV linear accelerator.
When the dose is delivered in presence of a magnetic
field, the Lorenz force will change the trajectories of the
high energy electrons generated by the megavoltage
radiation. The effect on dose distribution depends on the
magnetic field strength, its direction relative to the
treatment field and the energy. In our MRI-linac design
this results in a decreased build-up distance and a shifted
penumbra. Changes can also be observed in the dose
distribution near interfaces of two materials with
different densities. Especially near tissue-air boundaries
electrons can be curved back into the tissue (electron-
return-effect).
The influence of the magnetic field can also affect the
reading of various detectors used for reference dosimetry,
acceptance and commissioning, regular QA and patient
QA. The change in reading of a detector depends on the
field strength, orientation relative to the photon field and
the magnetic field and to sources of air-layers between
build-up material and detector.
An important detector is the waterproof farmer type
ionization chamber, which performance in a magnetic
field has been investigated thoroughly in our department.
Correction factors had been derived for the magnetic field
in various geometries and orientations to obtain absolute
dose measurements. The performance was characterized
in water as well as solid water phantoms. Also the use of
other detectors such as a diamond detector have been
investigated for use in magnetic fields.
To evaluate dose distributions of clinical plan delivery,
patient specific quality assurance can be performed using
various dedicated detectors, such as the Delta4 and