Anticancer therapy and apoptosis imaging
Early response prediction is considered an essential tool to obtain a more customized anticancer treatment because it allows for the identification of patients who will benefit most from a particular therapy and prevents the exposure of those patients to toxic, non-effective regimens. Recent discove...
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| Опубліковано в: : | Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Цитувати: | Anticancer therapy and apoptosis imaging / T.J. Yang, A. Haimovitz-Friedman, M. Verheij // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 269-276. — Бібліогр.: 94 назв. — англ. |
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Yalcin, T.J. Haimovitz-Friedman, A. Verheij, M. 2018-06-19T18:45:36Z 2018-06-19T18:45:36Z 2012 Anticancer therapy and apoptosis imaging / T.J. Yang, A. Haimovitz-Friedman, M. Verheij // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 269-276. — Бібліогр.: 94 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139046 Early response prediction is considered an essential tool to obtain a more customized anticancer treatment because it allows for the identification of patients who will benefit most from a particular therapy and prevents the exposure of those patients to toxic, non-effective regimens. Recent discoveries of novel markers in functional imaging have created exciting opportunities for in vivo visualization and quantification of cell death. This review will focus on in vivo apoptosis imaging with various radiotracers as predictive tools for tumor response after anticancer therapy. Particular focus will be on annexin V imaging, a technique with the largest clinical experience to date. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Anticancer therapy and apoptosis imaging Article published earlier |
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Anticancer therapy and apoptosis imaging |
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Anticancer therapy and apoptosis imaging Yalcin, T.J. Haimovitz-Friedman, A. Verheij, M. Reviews |
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Anticancer therapy and apoptosis imaging |
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Anticancer therapy and apoptosis imaging |
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Anticancer therapy and apoptosis imaging |
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Anticancer therapy and apoptosis imaging |
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anticancer therapy and apoptosis imaging |
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Yalcin, T.J. Haimovitz-Friedman, A. Verheij, M. |
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Yalcin, T.J. Haimovitz-Friedman, A. Verheij, M. |
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2012 |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Early response prediction is considered an essential tool to obtain a more customized anticancer treatment because it allows for the identification of patients who will benefit most from a particular therapy and prevents the exposure of those patients to toxic, non-effective regimens. Recent discoveries of novel markers in functional imaging have created exciting opportunities for in vivo visualization and quantification of cell death. This review will focus on in vivo apoptosis imaging with various radiotracers as predictive tools for tumor response after anticancer therapy. Particular focus will be on annexin V imaging, a technique with the largest clinical experience to date. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
|
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1812-9269 |
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https://nasplib.isofts.kiev.ua/handle/123456789/139046 |
| citation_txt |
Anticancer therapy and apoptosis imaging / T.J. Yang, A. Haimovitz-Friedman, M. Verheij // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 269-276. — Бібліогр.: 94 назв. — англ. |
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AT yalcintj anticancertherapyandapoptosisimaging AT haimovitzfriedmana anticancertherapyandapoptosisimaging AT verheijm anticancertherapyandapoptosisimaging |
| first_indexed |
2025-11-26T01:39:37Z |
| last_indexed |
2025-11-26T01:39:37Z |
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1850600439887691776 |
| fulltext |
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
ANTICANCER THERAPY AND APOPTOSIS IMAGING
T.J. Yang1, A. Haimovitz-Friedman1, M. Verheij2,*
1Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
2Department of Radiation Oncology and Division of Biological Stress Response, The Netherlands Cancer
Institute – Antoni van Leeuwenhoek Hospital, 1066 CX, Amsterdam, The Netherlands
Early response prediction is considered an essential tool to obtain a more customized anticancer treatment because it allows for
the identification of patients who will benefit most from a particular therapy and prevents the exposure of those patients to toxic,
non-effective regimens. Recent discoveries of novel markers in functional imaging have created exciting opportunities for in vivo
visualization and quantification of cell death. This review will focus on in vivo apoptosis imaging with various radiotracers as predic-
tive tools for tumor response after anticancer therapy. Particular focus will be on annexin V imaging, a technique with the largest
clinical experience to date. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
Key Words: apoptosis, cell death, imaging, anticancer therapy, annexin V.
INTRODUCTION
Apoptosis is an evolutionary highly preserved and
well-orchestrated �iological process involved in �oth
physiological and pathological conditions� and there-
fore possi�ly the most a�undant form of programmed
cell death [�]. Therapy-induced apoptosis in vivo
has �een shown to significantly contri�ute to tumor
response [�� �] and to correlate with su�sequent
outcome [���]. After �� years of intense research�
apoptosis is now considered not only as a fundamental
process leading to disorders of normal tissues [����]�
�ut also as a form of cell death in response to oncolytic
therapies [�����].
Apoptosis can �e triggered �y exogenous and
endogenous stimuli leading to the activation of the ex-
trinsic and intrinsic pathways of apoptosis� respectively
�Fig. ��. These pathways converge at the activation
of a su�set of proteases� the executioner caspase-��
-� and -�� targeting specific intracellular proteins such
as those involved in DNA damage repair and cellular
cytoskeleton.
The extrinsic pathway is engaged �y �inding of spe-
cific death ligands to specific death receptors on the
cell mem�rane� such as tumor necrosis factor a �TNF-
a�� TNF-related apoptosis-inducing ligand �TRAIL��
Fas ligand �FasL� to TNF receptor � �TNFR��� death
receptor � or death receptor 5 �DR� or DR5� and Fas/
CD�5 receptor� respectively. Death receptor-ligand
�inding recruits an intracellular adaptor molecule�
TNF-receptor-associated death domain �TRADD�
or Fas-associated death domain �FADD� via its cy-
toplasmic death domain �DD�� clustering to form the
death-inducing signaling complex �DI�C� which in turn
recruits and activates cytoplasmic pro-apoptotic cas-
pase-8 �initiator caspase� via its death effector domain
�DED�. This is followed �y the sequential activation
of downstream executioner caspase-�� -�� and -�.
Activated caspase-� translocates to the nucleus and
activates poly-ADP-ri�ose polymerase �PARP-���
which facilitates the degradation of nuclear DNA into
5� to ��� kilo�ase-sized fragments.
Anticancer drugs and ionizing radiation utilize the
intrinsic pathway to trigger apoptosis. This process
involves mitochondrial outer mem�rane permea�ili-
zation and the su�sequent release of pro-apoptotic
factors� including cytochrome c� into the cytosol. Cy-
tochrome c interacts with Apaf-� �apoptotic activating
factor-��� ATP� and procaspase-� to form a complex
known as the apoptosome which in turn activates
caspase-� and further activates the executioner cas-
pase-�� -�� and -�� generating a variety of molecular
damages in essentially every organelle. In terms of cell
survival� however� it is the damage to DNA leading
to the loss of proliferative and clonogenic capac-
ity that is most important. Although chemotherapy
and radiotherapy-induced apoptosis is a caspase-
dependent process [�5��8]� it is unclear how cel-
lular signals from DNA lesions lead to the execution
of apoptosis. �ince Bcl-� is a�le to �lock cytochrome
c release and prevent apoptosis� it has �een proposed
that anticancer therapy-induced caspase activation
is mitochondria dependent [��� �����]. This concept
Received: June 25, 2012
*Correspondence: Phone: +31 20 512-21-20
Fax: +31 20 669-11-01
E-mail: m.verheij@nki.nl
Abbreviations used: 99mTc – 99mTechnetium; Apaf-1 – apoptotic
activating factor-1; BTAP – 4,5-bis(thioacetamido)pentanoyl;
CT – computed tomography; DD – death domain; DED – death
effector domain; DISC – death-inducing signaling complex;
DR – death receptor; FADD – Fas-associated death domain;
FasL – Fas ligand; HL – Hodgkin lymphoma; HNSCC – head and
neck squamous cell carcinoma; HYNIC – hydrazinonicotinamide;
MDR1 – multidrug resistance gene 1; MIBI – methoxyisobutyliso-
nitrile; NHL – non-Hodgkin lymphoma; NSCLC – non-small cell
lung cancer; PARA – pro-apoptotic receptor agonist; PARP-1 –
poly-ADP-ribose polymerase 1; PET – positron emission tomog-
raphy; PS – phosphatidylserine; SCLC – small cell lung cancer;
SPECT – single photon emission computerized tomography;
TAVS – 99mTc-annexin V scintigraphy; TNF-a – tumor necrosis
factor a; TNFR1 – TNF receptor 1; TRADD – TNF-receptor-as-
sociated death domain; TRAIL – TNF-related apoptosis-inducing
ligand; TUNEL – terminal deoxynucleotidyl transferase-mediated
dUTP–biotin nick end labeling.
Exp Oncol ����
��� �� �������
INVITED REVIEW
��� Experimental Oncology ��� �������� ���� ��eptem�er�
is further su�stantiated �y the o�servation that activa-
tion of p5� �y anticancer therapy due to DNA damage
is a direct transcriptional regulator of Bcl-�� Bax� Puma�
Noxa and Bid and can act as an apoptogenic factor
at the mitochondrial mem�rane [����5]. Furthermore�
there are functional connections �etween p5� and
death receptors genes �CD�5 and TRAIL receptor-��
that can �e upregulated in response to therapy [���
��]� in turn leading to the activation of inducer cas-
pase-8. It has also �een shown that pretreatment
of cells with DNA damaging agents improves the ca-
pacity of TRAIL-�ound receptors to recruit FADD and
activate caspase-8 and -�� in the DI�C� irrespective
of p5� status [�8].
As apoptosis has �een recognized as a major
form of cell death after anticancer therapy� it is �eing
increasingly evaluated as a prognostic marker of treat-
ment outcome. For this purpose� a noninvasive method
to analyze treatment-induced apoptosis is most at-
tractive� as it can �e used to determine and predict the
effectiveness of an anticancer regime. In this review�
we will discuss apoptosis imaging modalities in �oth
animal models and patients using annexin V� detection
of apoptotic mem�rane imprint� methoxyiso�utylisoni-
trile �MIBI�� and the novel caspase-� small-molecule
inhi�itor� Isatin� and address their a�ility to improve
patient treatment �see Fig. ��. Annexin V scintigraphy�
an imaging technique for which we have the most clini-
cal experience with� will especially �e detailed in this
discussion.
IMAGING OF APOPTOSIS USING ANNEXIN V
Annexin V-�ased tracers are the most frequently
used agents for in vitro detection and quantification
of apoptotic cells. This is �ased on the high affinity
of annexin V for the mem�rane �ound phospholipid
�P��� which in via�le cells� resides in the inner leaflet
of the plasma mem�rane. Upon exposure of cells
to apoptotic stimuli g-scram�lase is activated result-
ing in P� flipping to the outer leaflet of the plasma
mem�rane� there�y allowing annexin V to �ind
to P�. In addition� it has �een shown that mem-
�rane �inding of proteins that recognize exposed
P� on apoptotic cells is regulated �y the transmem-
�rane potential [��]. A decreasing mem�rane potential
in Jurkat T leukemia cells and K5�� promyelocytic
leukemia cells undergoing apoptosis increases the
extracellular �inding of annexin V in a dose-dependent
manner. �tudies with P� vesicles also showed that
the mem�rane potential increases the �inding affinity
of annexin V for the P� cell surface molecules.
Single photon emission computed tomography
(SPECT)
��mTechnetium-linked annexin V has �een exten-
sively used in apoptosis detection in patients� exploit-
ing its optimal radionuclidic properties for �PECT
Fig. 1. Imaging of apoptosis �y various radiotracers. While annexin V �ased compounds and Apo�ense agents work at the
level of the cell plasma mem�rane� MIBI acts at the mitochondria and Isatin targets executioner caspase � �DR=Death Receptor;
PARA=Pro-Apoptotic Receptor Agonist�. Inserts are examples of images acquired �y the indicated modalities. Modified from:
Haimovitz-Friedman et al.� ���� [��]
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
imaging� relative low costs and easy availa�ility [��].
In ���5� �tratton et al. [��] were the first to demon-
strate ��mTc-annexin V’s value for the in vivo detection
of mem�rane-associated P� exposure using �PECT
�y injecting ��mTc-la�eled human annexin V intrave-
nously and calculating the atrial throm�us/�lood ratio
in throm�o-em�olic diseases. Other �PECT studies
using ��mTc-annexin V derivatives provided feasi�i-
lity and potential clinical utility of apoptosis imaging
in various other medical disorders [��]. Multiple con-
jugators of annexin V have �een developed� including
��5-�is�thioacetamido�pentanoyl �BTAP� for its rapid
and extensive radioactivity accumulation in the gastro-
intestinal tract. �ince this tracer was mainly excreted
�y the liver and the kidneys� resulting in an increased
radionuclide accumulation in these organs as well
[��]� the role of ��mTc-BTAP annexin V for a�dominal
imaging was limited.
Blanken�erg et al. [��] su�sequently coupled
annexin V to hydrazinonicotinamide and created
��mTc-HYNIC annexin V. In vivo studies using a CD�5L-
induced hepatocyte apoptosis mouse model with
intravenously administered anti-CD�5 anti�ody dem-
onstrated that ��mTc-HYNIC annexin V can �e used
to image apoptotic �and necrotic� cell death in vivo.
Although the concentration of tracer in liver and
kidneys were still high� and similar to ��mTc-BTAP an-
nexin V� radioactivity accumulation in the �owel was
eradicated� making it a suita�le candidate tracer
for a�dominal examination [�5]. Following further
optimization of image quality� ��mTc-annexin V proves
to �e an effective modality for non-invasive evalua-
tion of cell death and treatment response in allograft
rejection� myocardial infarction� reperfusion injury and
infectious disease [����8].
99mTc-annexin V studies in combination with
anticancer therapy
The first in vivo demonstration of anticancer therapy-
induced apoptosis involved the use of ��mTc-annexin
V in an experimental mouse lymphoma model treated
with cyclophosphamide. The animals treated with che-
motherapy demonstrated a more than ���% increase
in annexin V uptake �� h after treatment compared
to untreated animals [��]. More recently� the value
of ��mTc-annexin V imaging in response monitoring
was evaluated in a mouse model for hereditary �reast
cancer after docetaxel treatment [��]. The sensitive
tumors showed an increase in ��mTc-annexin V uptake
and immunohistochemical evidence of apoptosis one
day post-treatment. On the other hand� resistant tumors
showed neither an increase in ��mTc-annexin V uptake
nor significant immunohistochemical changes �Fig. ��.
Despite these encouraging findings� ��mTc-annexin
V ima ging could not �e used to predict tumor response�
due to large variations in uptake �etween animals.
In addition to animal studies� annexin V imaging has
also �een applied in various clinical protocols. In �����
��mTc-annexin V was first used in clinical trials with pa-
tients scheduled to receive chemotherapy for locally
advanced or metastatic non-small cell lung cancer
�N�CLC�� small cell lung cancer ��CLC�� Hodgkin �HL�
and non-Hodgkin �NHL� lymphoma� and �reast cancer.
Fifteen patients underwent ��mTc-annexin V scintigra-
phy �efore and within � days after their first course
of chemotherapy. Patients with lung cancer received
platinum-�ased chemotherapy� lymphoma patients
were treated with vincristine or cyclophosphamide-
�ased chemotherapy and �reast cancer patients
received taxane as their chemotherapy regime. Five
patients had increased annexin V uptake ����8 hours
after chemotherapy �� NHL� � HL� � �CLC� and
� N�CLC�� and � patients showed increased uptake
����� hours after treatment �� N�CLC� � �CLC�.
At the median follow-up of ��� days� while patients
with no change in radiotracer uptake after the first
cycle of chemotherapy had no su�sequent o�jective
clinical response� patients demonstrating increased
tracer uptake post-treatment had either a partial
or complete tumor response. From these results� it was
concluded that ��mTc-annexin V could �e used clini-
cally for in vivo imaging of apoptosis after one course
of chemotherapy [��].
a
b
T*23 sensitive tumor
T*23 resistant tumor
Fig. 2. Preclinical imaging of apoptosis. Quantitative whole ani-
mal ��mTc-annexin V �PECT imaging and histology of a T*�� sen-
sitive �a� and resistant tumor �b�� o�tained �efore and � day after
docetaxel treatment. Right panel: tumors were stained for TUNEL
at day �. Modified from: Beekman et al.� ���� [��]
One of the first reports on the application of ��mTc-
annexin V in patients receiving radiotherapy was
�y Haas et al. [��] who applied ��mTc-annexin V scin-
tigraphy �TAV�� to monitor radiation-induced apoptotic
cell death in �� follicular lymphoma patients �Fig. ��. All
patients underwent a �aseline scan within one week
prior to the start of radiotherapy to detect �aseline
levels of spontaneous tumor apoptosis or necrosis. Pa-
tients were then irradiated to the involved lymph node
areas to a total dose of � Gy in � fractions �8 h apart.
At �� h after the second radiation fraction� TAV� was
repeated. Fine needle aspiration cytologic analysis
for apoptosis was also performed prior to� during and
after irradiation. In �� patients� post-treatment TAV�
��� Experimental Oncology ��� �������� ���� ��eptem�er�
matched the post-treatment cytology� confir ming
TAV� as a valua�le non-invasive method to detect
in vivo apoptosis caused �y radiation. In addition� the
increase in ��mTc-annexin V uptake post-treatment
in this type of malignancy correlated with clinical
outcome: all patients with prominent cytologic and
scintigraphic signs of apoptosis achieved complete
remission within � week.
In ����� Kartachova et al. [��] from the Nether-
lands Cancer Institute conducted a study of �� patients
with malignant lymphoma� leukemia� N�CLC� and head
and neck squamous cell carcinoma �HN�CC� sched-
uled for radiotherapy� platinum-�ased chemotherapy�
or concurrent chemoradiation �see Fig. ��.
Fig. 3. Typical examples of anticancer therapy-induced apop-
tosis as demonstrated �y in vivo annexin V scintigraphy. �hown
are � examples of �PECT �efore �left panel� and early during
treatment �i.e. ����8 h after start of therapy; right panel�. Upper
panel: NHL treated �y low dose ��x� Gy� involved-field radiation.
Middle panel: HN�CC treated �y cisplatin-�ased chemora-
diation. Lower panel: N�CLC treated �y cisplatin/gemcita�ine
chemotherapy. Arrows indicate the target lesions. Note the physi-
ologic uptake in �ones and salivary glands �Modified from: Haas
et al.� ���� [��] and Kartachova et al.� ���� [��]� Kartachova
et al.� ���� [��]� and Verheij et al.� ���8 [��]
The investigators demonstrated increased ��mTc-
annexin V accumulation in lesions early during treat-
ment when compared to �aseline values in patients
with complete or partial tumor remission� while there
was no significant early increase in uptake in those pa-
tients with sta�le or progressive disease. This study es-
ta�lished ��mTc-annexin V scintigraphy as a predictive
marker in tumor response. A su�sequent study from
these authors evaluated the predictive value of TAV�
in �� chemotherapy-naive patients with advanced
stage N�CLC undergoing platinum-�ased chemo-
therapy. Also under these conditions� a significant
correlation �etween annexin V changes and treatment
outcome was found [��]. In a ���8 update of their
study� Kartachova et al. [�5] showed that visual evalu-
ation of �PECT images� �PECT/�PECT and �PECT/
CT co-registered images correlated with quantitative
analysis. Using �oth methods� all patients with early
post-treatment increase in tumor uptake of ��mTc-an-
nexin V either developed complete response or partial
response� resulting in statistically highly significant
correlations �etween changes of ��mTc-annexin V tu-
mor uptake and therapeutic outcome for �oth visual
and quantitative analysis.
In addition to the monitoring of treatment-induced
apoptosis in tumor cells� TAV� may also �e used
to detect normal tissue toxicity. Hoe�ers et al. [��]
applied ��mTc-annexin V scintigraphy to demonstrate
apoptosis in patients with HN�CC� �oth in tumor
and normal tissue. TAV� was performed �efore and
within �8 h after the first course of cisplatin-�ased
chemoradiation in �� patients. Already after a dose
of ��8 Gy increased annexin V uptake was o�served
in �� of the �� irradiated parotid glands. Glands� which
received higher radiation dosages� showed more an-
nexin V uptake. The authors concluded that within
the dose range of ��8 Gy� TAV� showed a radiation-
dose-dependent uptake in parotid glands� indicative
of radiation-induced apoptosis. A similar pattern in the
su�mandi�ular glands was o�served.
Limitations of annexin V imaging
Although TAV� appears very promising as an early
predictor for tumor response to anticancer therapy�
several limitations remain to firmly esta�lish its value
as an imaging �iomarker of response. First of all�
apoptosis is an acute event and contri�utes to early
therapy-induced tumor shrinkage. Therefore� TAV�
may �e less suita�le to predict long-term response
to treatment [�����]. To determine whether this type
of early cell death predicts long-term treatment out-
come parameters in patients� such as disease-free
survival and overall survival� changes in TAV� uptake
should �e correlated with tumor response measure-
ments after sufficiently long follow-up. �econdly� an-
nexin V �inding to P� does not discriminate �etween
apoptotic and necrotic cell death as disrupted plasma
mem�ranes also make P� accessi�le at the inner
leaflet of cells undergoing necrosis. Thirdly� in terms
of �iodistri�ution� annexin V has a relatively slow clear-
ing rate from non-targeted tissues� therefore creating
a low signal-to-noise ratio [5�]. Fourthly� the optimal
timing of apoptosis-imaging in vivo that yields most
predictive information in terms of tumor response
remains uncertain and should ideally �e determined
for each specific tumor type and treatment moda-
lity. Multiple TAV� measurements may �e necessary
to define this tumor- and/or therapy-specific optimal
timing. Finally� apoptosis represents only one aspect
of the complex �iological response to therapy� and
its relative contri�ution varies among different tumor
entities. More studies are needed to demonstrate the
applica�ility of TAV�� especially in �solid� tumors that
are therapy-resistant. Com�ining TAV� with other
anatomical and functional imaging modalities may
�e helpful in o�taining a more complete� and perhaps
more solid �iomarker.
OTHER RADIOTRACERS IN APOPTOSIS
IMAGING
Detection of apoptotic membrane imprint
The apoptotic mem�rane imprint is a complex of cel-
lular changes occurring in the plasma mem�rane early
during the apoptotic process. These include irreversi�le
loss of mem�rane potential� permanent acidification
of the external plasma mem�rane leaflet and cytosol�
and activation of g-scram�lase while preserving the
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
integrity of the plasma mem�rane. A set of novel small-
molecule pro�es designated the Aposense compounds
�Aposense Ltd.� Petach-Tikva� Israel� have �een devel-
oped to detect these apoptosis-related plasma mem-
�rane alterations �see Fig. � [5�]�. This family of small
molecules �DDC� ML-��� ML-�� N�T-���� and N�T-
���� have demonstrated activities in a num�er of tumor
models in response to anticancer agents [5��5�]�
however there is no clear mechanism of uptake of these
compounds. The positron emission tomography �PET�
tracer �8F-ML-�� shows selective uptake �y apoptotic
cells in tumors following radio- and chemotherapy� cor-
relating with �reakdown of mitochondrial mem�rane
potential� caspase activation and DNA degradation.
As the signal is lost upon rupture of the plasma mem-
�rane� �8F-ML-�� should �e capa�le of discriminating
apoptotic from necrotic cells [5�].
Recently� the role of �8F-ML-�� was evaluated
in the early detection of response of �rain metasta-
ses to whole �rain irradiation ���x� Gy�. In this study
�� patients underwent an �8F-ML-�� PET scan prior
to treatment and a second scan after � or �� fractions
of radiation. MRI was performed ��8 weeks after
completion of treatment. In all �� patients� �oth MRI
and the �8F-ML-�� PET scan detected all �rain lesions.
A highly significant correlation was found �etween
early changes on the �8F-ML-�� scan and later changes
in tumor anatomical dimensions on MRI [55].
Methoxyisobutylisonitrile (MIBI)
Technetium-��m methoxyiso�utylisonitrile ���mTc-
MIBI� is a lipophilic cation isonitrile compound that
crosses the cell mem�rane due to the negative trans-
mem�rane potential and accumulates in mitochondria
[5�� 5�]. Because of their higher meta�olic activity�
tumor cells show large differences in mitochondrial
mem�rane potential and high num�ers of mitochon-
dria� making ��mTc-MIBI an attractive agent in tumor
imaging �see Fig. ��. Indeed� studies have demon-
strated that good responders of anti-tumor treatment
display more MIBI accumulation as compared to poor
responders in various tumor types� including small cell
and non-small cell lung cancer [58���]� �reast cancer
[�5]� malignant lymphoma [��]� osteosarcoma [��]�
and nasopharyngeal carcinoma [�8]. One explanation
for this phenomenon could �e the overexpression
of the multidrug resistance gene �MDR��� which en-
codes P-glycoprotein �Pgp�� a transmem�rane protein
that acts as an efflux pump to a wide range of cyto-
toxic drugs and ��mTc-MIBI [����5]� in chemotherapy
resistant tumors. Another possi�ility is the inhi�ition
of mitochondrial mem�rane permea�ility as a result
of the overexpression of anti-apoptotic proteins
such as Bcl-� [��� ��]. More recently� studies have
esta�lished a correlation �etween ��mTc-MIBI tumor
cell uptake and apoptosis after irradiation or che-
motherapy [�8� ��]. In an unpu�lished study� Del
Vecchio et al. [��] demonstrated that the overex-
pression of Bcl-� which prevented ��mTc-MIBI uptake
in untreated �reast carcinoma could �e counteracted
�y the initiated drug therapy� allowing a transient in-
crease in ��mTc-MIBI accumulation. The authors specu-
lated that altered expression of proteins participating
in the apoptotic process would affect mitochondrial
permea�ility and transmem�rane potential� leading
to a change in intracellular ��mTc-MIBI accumulation
�oth prior to and after initiation of therapy. Further-
more� high levels of early ��mTc-MIBI uptake after
treatment [8�]� could potentially indicate therapeutic
efficacy. These results suggest that ��mTc-MIBI scin-
tigraphy has important clinical implications in pro-
viding prognostic information prior to treatment and
also in monitoring effectiveness of treatment after
initiation of anticancer therapy.
Caspase-3 tracers
�everal groups have developed novel PET pro�es
designed to non-invasively image caspase-� activa-
tion� including the small-molecule caspase inhi�itor�
Isatin� used with different radioisotopes �see Fig. ��.
�everal of these ��C or �8F Isatins examined in vivo
[8��8�] demonstrated high affinity to caspase-� and
high uptake in the liver in response to cycloheximide
or anti-CD�5 anti�ody� confirmed �y immunohistol-
ogy of cell death. Although the radiola�eled Isatins
appear to �ind specifically to caspase-�� their sen-
sitivity is limi ted� indicating that further optimization
is required for clinical application of these tracers.
Coppola et al. [88] generated sta�le cell lines
transfected with a hy�rid luciferase reported construct�
which is activated �y caspase-� cleavage. Using
this system� the apoptotic response of D5� glioma
xenograft tumors to temozolomide and radiation was
monitored �y detecting �ioluminescence emission.
Apoptosis was detected within � h after � Gy of ra-
diation in mice receiving the com�ination treatment.
Although this method appeared to �e very sensitive
and quantitative� the experience seemed to �e lim-
ited to several animal models [85� 8�]. No pu�lished
patient data are availa�le thus far. In addition� it has
recently �een found that caspase-� activation is not
unique to apoptosis [��� ��] and is involved in other
physiological processes such as platelet aggregation
and secretion of enzymes from pancreatic acinar cells.
CONCLUDING REMARKS
This review focuses on in vivo apoptosis imag-
ing as a clinical �iomarker of response to treatment.
In evaluating radiotracers for apoptosis imaging� there
are a num�er of issues to consider. First� the tumor
is heterogeneous and consists of a mixture of different
cell types and no tracer discussed displays sufficient
specificity to identify su�populations of tumor cells
undergoing primary apoptosis. In fact� different types
of cell death can �e induced �y anticancer therapy and
exist within the same tumor� including “secondary”
apoptosis due to incomplete DNA damage repair �after
“mitotic death” or “mitotic catastrophe” or “reproduc-
tive cell death” [��� ��]�. �econd� �ecause response
to therapy is tumor type-dependent� the optimal timing
of in vivo imaging remains to �e defined. Though ��mTc-
annexin V scintigraphy has emerged as an attractive
��� Experimental Oncology ��� �������� ���� ��eptem�er�
candidate due to its predictive potential in treatment
effectiveness in various tumor types� it is not an exclu-
sive marker for this type of cell death� as cellular ne-
crosis accommodates �inding of annexin V to exposed
mem�rane P� as well. Therefore� further studies are
needed to evaluate the applica�ility of this and other
potential apoptotic markers in daily clinical practice.
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