Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon
In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer — an immunoconjugate of hematoporphyrin with antiVE...
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| Zitieren: | Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon / N.F. Gamaleia, I.A. Lisnyak, E.D. Shishko, A.A. Mamchur, I.V. Prokopenko, V.V. Kholin // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 364-366. — Бібліогр.: 11 назв. — англ. |
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irk-123456789-1398602018-06-22T03:05:03Z Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon Gamaleia, N.F. Lisnyak, I.A. Shishko, E.D. Mamchur, A.A. Prokopenko, I.V. Kholin, V.V. Short communications In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer — an immunoconjugate of hematoporphyrin with antiVEGF antibodies. Aim: To elaborate and to test a novel modification of the photodynamic therapy of tumors (PDT) method, founding upon a timed introduction of the immunoconjugated photosensitizer to tumor-bearing animals, so that this coincides with a maximum content of VEGF in tumor tissues. Methods: Circadian variations of VEGF contents in murine transplanted tumors, Lewis lung carcinoma and sarcoma 180, were determined by ELISA method. Immunoconjugated photosensitizer concentrations in tumors were estimated by spectrofluorometry. Photoirradiation of the tumors was carried out with a red light (wavelength of 635 nm) from a semiconductor laser. Light doses were chosen, calculating on a partial inhibition of tumor growth, in order that a dependence of PDT efficiency on a daily time-moment (circadian rhythm phase) of the treatment could be observed distinctly. Results: Circadian variations of the VEGF levels in Lewis lung carcinoma and sarcoma 180 were demonstrated with the maximum at 14:00 h and the minimum at 02:00 h. Intra-abdominal introduction into tumor-bearing mice of the immunoconjugated photosensitizer resulted in a greater accumulation of the immunoconjugate in tumors at 14:00 h than at 02:00 h. Laser irradiation of carcinomas and sarcomas at 14:00 h or 02:00 h after introduction of the immunoconjugated photosensitizer to mice the day before at the same time points, induced a significantly enhanced inhibition of tumor growth in animals treated at day-time versus those treated at night-time. Conclusion: The obtained results justify further attempts to transfer principles of tumor chronochemotherapy onto photodynamic therapy. 2012 Article Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon / N.F. Gamaleia, I.A. Lisnyak, E.D. Shishko, A.A. Mamchur, I.V. Prokopenko, V.V. Kholin // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 364-366. — Бібліогр.: 11 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/139860 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Short communications Short communications Gamaleia, N.F. Lisnyak, I.A. Shishko, E.D. Mamchur, A.A. Prokopenko, I.V. Kholin, V.V. Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon Experimental Oncology |
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In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer — an immunoconjugate of hematoporphyrin with antiVEGF antibodies. Aim: To elaborate and to test a novel modification of the photodynamic therapy of tumors (PDT) method, founding upon a timed introduction of the immunoconjugated photosensitizer to tumor-bearing animals, so that this coincides with a maximum content of VEGF in tumor tissues. Methods: Circadian variations of VEGF contents in murine transplanted tumors, Lewis lung carcinoma and sarcoma 180, were determined by ELISA method. Immunoconjugated photosensitizer concentrations in tumors were estimated by spectrofluorometry. Photoirradiation of the tumors was carried out with a red light (wavelength of 635 nm) from a semiconductor laser. Light doses were chosen, calculating on a partial inhibition of tumor growth, in order that a dependence of PDT efficiency on a daily time-moment (circadian rhythm phase) of the treatment could be observed distinctly. Results: Circadian variations of the VEGF levels in Lewis lung carcinoma and sarcoma 180 were demonstrated with the maximum at 14:00 h and the minimum at 02:00 h. Intra-abdominal introduction into tumor-bearing mice of the immunoconjugated photosensitizer resulted in a greater accumulation of the immunoconjugate in tumors at 14:00 h than at 02:00 h. Laser irradiation of carcinomas and sarcomas at 14:00 h or 02:00 h after introduction of the immunoconjugated photosensitizer to mice the day before at the same time points, induced a significantly enhanced inhibition of tumor growth in animals treated at day-time versus those treated at night-time. Conclusion: The obtained results justify further attempts to transfer principles of tumor chronochemotherapy onto photodynamic therapy. |
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Article |
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Gamaleia, N.F. Lisnyak, I.A. Shishko, E.D. Mamchur, A.A. Prokopenko, I.V. Kholin, V.V. |
| author_facet |
Gamaleia, N.F. Lisnyak, I.A. Shishko, E.D. Mamchur, A.A. Prokopenko, I.V. Kholin, V.V. |
| author_sort |
Gamaleia, N.F. |
| title |
Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon |
| title_short |
Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon |
| title_full |
Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon |
| title_fullStr |
Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon |
| title_full_unstemmed |
Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon |
| title_sort |
chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluation |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2012 |
| topic_facet |
Short communications |
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http://dspace.nbuv.gov.ua/handle/123456789/139860 |
| citation_txt |
Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluatIon / N.F. Gamaleia, I.A. Lisnyak, E.D. Shishko, A.A. Mamchur, I.V. Prokopenko, V.V. Kholin // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 364-366. — Бібліогр.: 11 назв. — англ. |
| series |
Experimental Oncology |
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| fulltext |
364 Experimental Oncology 34, 364–366, 2012 (December)
CHRONOBIOLOGICAL APPROACHES TO ANTIANGIOGENIC
PHOTODYNAMIC THERAPY OF TUMORS: THE FIRST
EXPERIMENTAL EVALUATION
N.F. Gamaleia1*, I.A. Lisnyak1, E.D. Shishko1, A.A Mamchur1, I.V. Prokopenko1, V.V. Kholin2
1Kavetsky Institute for Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kiev 03022, Ukraine
2SME “Photonika Plus”, Cherkassy 18023, Ukraine
In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were
discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer — an immunoconjugate
of hematoporphyrin with antiVEGF antibodies. Aim: To elaborate and to test a novel modification of the photodynamic therapy of tumors
(PDT) method, founding upon a timed introduction of the immunoconjugated photosensitizer to tumor-bearing animals, so that this
coincides with a maximum content of VEGF in tumor tissues. Methods: Circadian variations of VEGF contents in murine transplanted
tumors, Lewis lung carcinoma and sarcoma 180, were determined by ELISA method. Immunoconjugated photosensitizer concentrations
in tumors were estimated by spectrofluorometry. Photoirradiation of the tumors was carried out with a red light (wavelength of 635 nm)
from a semiconductor laser. Light doses were chosen, calculating on a partial inhibition of tumor growth, in order that a dependence
of PDT efficiency on a daily time-moment (circadian rhythm phase) of the treatment could be observed distinctly. Results: Circadian
variations of the VEGF levels in Lewis lung carcinoma and sarcoma 180 were demonstrated with the maximum at 14:00 h and the mini-
mum at 02:00 h. Intra-abdominal introduction into tumor-bearing mice of the immunoconjugated photosensitizer resulted in a greater
accumulation of the immunoconjugate in tumors at 14:00 h than at 02:00 h. Laser irradiation of carcinomas and sarcomas
at 14:00 h or 02:00 h after introduction of the immunoconjugated photosensitizer to mice the day before at the same time points, induced
a significantly enhanced inhibition of tumor growth in animals treated at day-time versus those treated at night-time. Conclusion: The
obtained results justify further attempts to transfer principles of tumor chronochemotherapy onto photodynamic therapy.
Key words: circadian rhythm, circadian rhythm-guided PDT, chronotherapy, immunoconjugated hematoporphyrin, antibodies
to vascular endothelial growth factor.
Photodynamic therapy of tumors (PDT), a com-
paratively new, modern method of cancer treatment,
has a remarkable set of merits such as a considerable
selectivity of antitumor effects, a low invasiveness and
an absence of serious side reactions. However, due
to a poor penetration of light radiation into biological
tissues, the method practical application is rather
limited, and radical curative results with it are feasible
only in early stages of cancer, in tumors with a superfi-
cial type of growth, and so on. To partly overcome the
drawback, efforts are undertaken to synthesize com-
bined photosensitizers containing antibodies or other
biologically active agents (peptides, growth factors,
cytokines, etc) more or less specific for malignant
cells [1, 2]. Such photosensitizers are better accumu-
lated in tumor tissues, making them responsive even
to a scarce light that penetrates into a tumor depth.
Another way to obtain photosensitizers, targeted
to a site of tumor growth, is to conjugate them with an-
giogenic elements of vessels that are actively formed
in a growing tumor. In particular, the conjugates of pho-
tosensitizers with factors (inductors) of angiogenesis
or antibodies to them can be created. In this context,
our attention was drawn to the observations in which
rhythmic (circadian) character of a secretion by tu-
mors of a vascular endothelial growth factor (VEGF)
was established [3]. Since earlier we synthesized
and characterized a conjugate of hematoporphyrin
with antiVEGF as the means to enhance transporta-
tion of the photosensitizer into tumors [4, 5], we now
explored a possibility to raise efficiency of PDT with
this immunoconjugated photosensitizer by timing its
introduction in tumor-bearing animals relatively to the
circadian rhythm of VEGF secretion by tumors.
MATERIALS AND METHODS
Circadian variations of VEGF production were
studied in mice with transplanted tumors — Lewis
lung carcinoma and sarcoma 180. Two month old
male mice, bred in the animal facility of R.E. Kavetsky
Institute of Experimental Pathology, Oncology and
Radiobiology, NAS of Ukraine, were utilized. All animal
procedures were carried out according to the rules
of local Ethic Committee and were approved by the
Ethic Board of IEPOR NASU. The tumors were ex-
cised during 24 hours at four different time points:
at 08:00 h, 14:00 h, 20:00 h and 02:00 h. VEGF from
tumor samples was isolated and evaluated for the fac-
tor concentration and specifity by ELISA method using
recombinant VEGF-165 (Sigma, USA) and monoclonal
antiVEGF antibodies (Sigma, USA) as described in [6].
To synthesize the combined photosensitizers,
antibodies to VEGF were conjugated to hematopor-
phyrin dihydrochloride (Fluka, Netherlands) emploing
1-ethyl-3(3-dimethylaminopropyl)-carbodiimide-HCl
as a linker [7]. Molar ratio of anti-VEGF antibodies
to hematoporphyrin in the immonoconjugate was
Received: June 5, 2012.
*Correspondence: Fax: 8 044 258 16 56
E-mail: gamaleia@onconet.kiev.ua
Abbreviations used: ELISA — enzyme-linked immunosorbent as-
say; PDT — photodynamic therapy of tumors; VEGF — vascular
endothelial growth factor.
Exp Oncol 2012
34, 4, 364–366
SHORT COMMUNICATIONS
Experimental Oncology 34, 364–366, 2012 (December)34, 364–366, 2012 (December) (December) 365
estimated spectrophotometrically by absorption
at 280 nm and 505 nm, respectively.
To ascertain that accumulation of the hematopor-
phyrin-antiVEGF in tumors obeys circadian rhythmic-
ity, the immunoconjugated photosensitizer or free
hematoporphyrin (in a parallel control group) were
injected to mice intra-abdominally, 3 mg per mouse
of the immunoconjugate and 0.05 mg per mouse of the
free photosensitizer, so that doses of hematoporphyrin
were in both cases equal. Photosensitizer contents
in samples were determined by a hematoporphyrin
fluorescence (λmax 620, 680 nm, fluorospectrometer
Nanodrop 3300, USA) in tumor tissue samples after
their freezing in liquid nitrogen, mechanical homogeni-
zation and extraction with a methanol-water solution.
For circadian rhythm-guided PDT, two tumor models
of different histological origin were used: metastasiz-
ing Lewis lung carcinoma, transplanted into a foot pad
of C57Bl/6 mice, and non-metastasizing sarcoma 180,
transplanted under the skin of white outbred mice. The
therapy started when carcinomas reached a diameter
of 5–7 mm and sarcomas — 10 mm. The conjugated
photosensitizer (3.0 mg/mouse) or free hematoporphy-
rin (0.05 mg/mouse) were introduced intra-abdominally
at 14:00 h or 02:00 h, that is at time points of a maximum
and minimum accumulation of the immunoconjugated
photosensitizer, respectively, as it was preliminarily estab-
lished by experiments on determination of circadian varia-
tions in the VEGF production, described above. In 24 hours
after the photosensitizer introduction, tumors were treated
with red-light radiation (wavelength of 635 nm, power
density of 26 mW/cm2, dose of 30 J/cm2) from a semi-
conductor laser (Photonika Plus, Ukraine). A treatment
efficiency was estimated by excised tumor masses (Lewis
carcinoma) or by tumor sizes on the second, ninth and 12th
days after animal photoirradiation (sarcoma 180).
In all three series of animal experiments (on deter-
mination of a rhythmicity in the VEGF production /I/ and
in the immunoconjugated photosensitizer accumula-
tion /II/, as well as on the circadian rhythm-guided
PDT /III/), before every experiment was started, mice
were kept under continuous darkness for two weeks,
so that a free-running circadian rhythm set in. Then,
the regimen was switched to an alternation of light
and darkness (light from 08:00 h to 20:00 h, darkness
from 20:00 h to 08:00 h), and under these conditions
animals remained until the end of the experiment.
All the experiments were performed in autumnal
season (October — November).
For all data calculations the statistical t-test was used.
RESULTS AND DISCUSSION
Circadian variations of the VEGF content in tumors.
VEGF concentrations were determined for 24 h at four
different time points in the samples of tumor tissues, ob-
tained from mice with Lewis lung carcinoma or sarcoma
180. As a result, regular circadian fluctuations of the an-
giogenic factor production were observed: a maximum
content of the factor in tumors fell on the middle of the
day-time and a minimum — on the middle of night (Fig. 1).
0
1
2
3
4
5
6
7
8:00 14:00 20:00 2:00
VE
G
F
co
nt
en
t (
ng
/m
g
pr
ot
ei
n)
Sarcomа 180
Lewis carcinomа
Fig. 1. Circadian variations of the VEGF content in sarcoma 180 and
Lewis lung carcinoma. Data for every time point are presented as the
mean ± SD of three animals
Circadian character of the immunoconjugated
photosensitizer accumulation. The immunoconju-
gated photosensitizer hematoporphyrin-antiVEGF was
introduced to mice intra-abdominally at two different
time points: at 14:00 h or 02:00 h. Next day, at the
same time points, tumor samples were obtained, and
the accumulated photosensitizer fluorescence was
measured by spectrofluorometry. Fluorograms, pre-
sented in Fig. 2 and 3, show higher fluorescence levels
(and therefore, elevated photosensitizer accumulation)
at the time of VEGF production maximum (at 14:00 h),
in comparison with its minimum (at 02:00 h).
0
5
10
15
20
25
39
5
41
9
44
3
46
7
49
1
51
5
53
9
56
3
58
7
61
1
63
5
65
9
68
3
70
7
73
1
Wavelength (nm)
Fl
uo
re
sc
en
ce
in
te
ns
ity
(r
.u
.)
14:00
2:00
Fig. 2. Immunoconjugated photosensitizer fluorescence in Lew-
is carcinoma as a function of daily time-points (circadian rhythm
phases) exploited for the photosensitizer introduction/analysis
0
2
4
6
8
10
12
39
5
41
9
44
3
46
7
49
1
51
5
53
9
56
3
58
7
61
1
63
5
65
9
68
3
70
7
73
1
Wavelength (nm)
Fl
uo
re
sc
en
ce
in
te
ns
ity
(r
.u
.)
14:00
2:00
Fig. 3. Immunoconjugated photosensitizer fluorescence in sar-
coma 180 as a function of daily time-points (circadian rhythm
phases) exploited for the photosensitizer introduction/analysis
Circadian rhythm-guided photodynamic therapy.
Proceeding from the data on circadian variations of VEGF
production by tumors and on a synchronism of this
366 Experimental Oncology 34, 364–366, 2012 (December)
process with hematoporphyrin-antiVEGF accumulation
in tumor tissues, we carried out experiments on a rhythm-
guided PDT of Lewis carcinoma and sarcoma 180, using
the immunoconjugated photosensitizer. Parameters
of laser irradiation were chosen in anticipation of a partial
inhibition of tumor growth, so that a dependence of PDT
efficiency on a daily time-moment (circadian rhythm
phase) of the treatment could be observed distinctly.
As it is shown in Fig. 4, PDT treatment of mice with
carcinomas on a middle of the day-time (at 14:00 h), that
is at the time of the maximum in VEGF content, resulted
in significantly (p < 0.05) greater tumor growth inhibition
than the same treatment executed at 02:00 h of night
which corresponded to the time of the minimum in VEGF
content of tumor tissues. In the group of animals,
treated at the day-time, growth inhibition made 60.4%
comparing to control (untreated) animals, and in the
group with the night-time treatment it amounted to 45%.
0
20
40
60
80
100
120
140
160
180
200
Control Treatment
at 14:00 h
Treatment
at 2:00 h
Tu
m
or
w
ei
gh
t (
m
g)
*
Fig. 4. Circadian rhythm-guided PDT of Lewis carcinoma with
application of the immunoconjugated photosensitizer.
*The difference is significant as compared to both control and
02:00 h groups (p < 0.05)
Since in studies on the circadian rhythm-guided PDT
with another experimental tumor — sarcoma 180 treat- — sarcoma 180 treat-— sarcoma 180 treat- sarcoma 180 treat-sarcoma 180 treat-
ment efficiency was evaluated by a tumor size, there
was a possibility to follow the tumor growth dynamics.
In Fig. 5 the data obtained in these experiments are
presented. As it is seen from the data, tumor growth in-
hibition was again considerably more pronounced in the
group of mice, treated at 14:00 h. Virtually, tumors in this
group were not growing for whole the observation period.
**
0
2
4
6
8
10
12
14
16
Before
treatment
2 9 12
Time after treatment (days)
Tu
m
or
d
ia
m
et
er
, m
m
Control
Treatment at 14:00 h
Treatment at 02:00 h
Fig. 5. Circadian rhythm-guided PDT of sarcoma 180 with application
of the immunoconjugated photosensitizer.
*The difference is significant as compared to both control and
02:00 h groups (p < 0.05).
Thus, presented results apparently corroborate our
assumption that PDT application of the immunocon-
jugated photosensitizer hematoporphyrin-antiVEGF,
timed with the maximum in circadian variations of the
VEGF content in tumors, may open a fresh opportunity
for enhancing the therapy effectiveness. Although
chronobiological approaches to the chemotherapy
of tumors were already recognized for quite a long
time [8–10], such chronotherapeutic modifications
of PDT have not been, to our knowledge, proposed
before. Only very recently we have formulated basic
principles of the method which may be designated
as a chronophotodynamic therapy of tumors [11].
The promising results obtained in our study justify
further attempts to extend the principles of antitumor
chronochemotherapy to PDT. Moreover, so far as the
conjugated photosensitizers development is on the
rise, it probably makes sense to expand the research
scope, not confining it to the VEGF or angiogenic fac-
tors in general.
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