Antineoplastic therapy by radioactive cisplatin in experiment
The method of ¹⁹⁵mPt production on linear electron accelerators and cyclotron of NSC KIPT are described. The method of ¹⁹⁵mPt separation from the irradiated samples are developed. The methods of cisplatin synthesis with use of a radioactive isotope of ¹⁹⁵mPt are realized. Results of biological tests...
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| Date: | 2007 |
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Національний науковий центр «Харківський фізико-технічний інститут» НАН України
2007
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| Cite this: | Antineoplastic therapy by radioactive cisplatin in experiment / N.P. Dikiy, A.N. Dovbnya, Y.V. Lyashko, E.P. Medvedeva, D.V. Medvedev, V.L. Uvarov // Вопросы атомной науки и техники. — 2007. — № 5. — С. 118-121. — Бібліогр.: 13 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859785179916140544 |
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| author | Dikiy, N.P. Dovbnya, A.N. Lyashko, Y.V. Medvedeva, E.P. Medvedev, D.V. Uvarov, V.L. |
| author_facet | Dikiy, N.P. Dovbnya, A.N. Lyashko, Y.V. Medvedeva, E.P. Medvedev, D.V. Uvarov, V.L. |
| citation_txt | Antineoplastic therapy by radioactive cisplatin in experiment / N.P. Dikiy, A.N. Dovbnya, Y.V. Lyashko, E.P. Medvedeva, D.V. Medvedev, V.L. Uvarov // Вопросы атомной науки и техники. — 2007. — № 5. — С. 118-121. — Бібліогр.: 13 назв. — англ. |
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| container_title | Вопросы атомной науки и техники |
| description | The method of ¹⁹⁵mPt production on linear electron accelerators and cyclotron of NSC KIPT are described. The method of ¹⁹⁵mPt separation from the irradiated samples are developed. The methods of cisplatin synthesis with use of a radioactive isotope of ¹⁹⁵mPt are realized. Results of biological tests of radioactive cisplatin on animals are described. Our preliminary results demonstrate the feasibility of radioactive cisplatin for treatment of cancer diseases.
Розглядаються способи виробництва ¹⁹⁵mPt на лінійних прискорювачах електронів і циклотроні ННЦ ХФТІ. Розроблено методи виділення ¹⁹⁵mPt з опромінених зразків. Реалізовано методи синтезу цисплатину з використанням радіоактивного ізотопу ¹⁹⁵mPt. Наведено результати біологічних випробувань радіоактивного цисплатину на тваринах. Наші попередні результати демонструють можливість використання радіоактивного цисплатину для лікування канцерогенних захворювань.
Рассматриваются способы производства ¹⁹⁵mPt на линейных ускорителях электронов и циклотроне ННЦ ХФТИ. Разработаны методы выделения ¹⁹⁵mPt из облученных образцов. Реализованы методы синтеза цисплатина с использованием радиоактивного изотопа ¹⁹⁵mPt. Приведены результаты биологических испытаний радиоактивного цисплатина на животных. Наши предварительные результаты демонстрируют возможность использования радиоактивного цисплатина для лечения канцерогенных заболеваний.
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ANTINEOPLASTIC THERAPY BY RADIOACTIVE
CISPLATIN IN EXPERIMENT
N.P. Dikiy∗, A.N. Dovbnya, Y.V. Lyashko, E.P. Medvedeva,
D.V. Medvedev, V.L. Uvarov
National Science Center ”Kharkov Institute of Physics and Technology”, 61108, Kharkov, Ukraine
(Received March 23, 2007)
The method of 195mPt production on linear electron accelerators and cyclotron of NSC KIPT are described. The
method of 195mPt separation from the irradiated samples are developed. The methods of cisplatin synthesis with
use of a radioactive isotope of 195mPt are realized. Results of biological tests of radioactive cisplatin on animals
are described. Our preliminary results demonstrate the feasibility of radioactive cisplatin for treatment of cancer
diseases.
PACS: 29.17.+w, 28.41.Kw
1. INTRODUCTION
Last years new methods find expanding applica-
tion in the medical treatment of cancerous diseases.
One of the most promising approaches is brachyther-
apy. Generally it is the implantation of miniature
radioactive sources in the form of a thin wire, cap-
sules or little seeds. Implants are introduced either
after surgical operations for irradiation of residuary
malignant cells or by means of catheters. The main
isotopes used in brachytherapy are 103Pd, 125I, 192Ir,
106Ru, 198Au [1]. There are two types of brachyther-
apy: with low levels and with high levels of irra-
diation intensity. In the case of the high-intensity
brachytherapy a source is introduced directly into the
carcinoma for the definite time to attain a therapeutic
effect. Usually this type of brachytherapy is applied
for the cure of the malignant tumor of the lacteal
gland, lungs etc. The low-intensity brachytherapy,
for example, use of isotopes of 103Pd and 185Ir for the
therapy of early stages of adenoma cancer. The use of
open sources of radioisotopes in the nuclear medicine
is more effective. Several decades ago this method
was applied for the therapy of various cancerous dis-
eases. However, only during last years this method
finds more extensive use. It is conditioned by the de-
velopment of more effective methods of isotope trans-
port into the malignant tumor. It should be notice
also the use of labelled peptides and other receptor-
specific molecules, isotopes for the palliative therapy
of a pain in the case of osteal metastasizes, labeled an-
tibody agents, e.g. copper-containing monocarbonyl
porphine [2]. The radiopharmaceuticals under con-
sideration possess a high tropic sensitivity to some
tumors that can be effectively cured with the using
of the monocarbonylporphine labeling with 67Cu. A
particular attention is given to the methods of ther-
apy using the high-value losses of Auger electrons [3-
5]. It is known that the average number of Auger and
Coster-Kronig electrons for 111In, 123I, 125 is equal to
about 8, 11 and 20 electrons, respectively, with the
energy from 12 to 24 keV. Deceleration of these elec-
trons leads to the energy release in a negligible vol-
ume (a few cubic nm) and, as a result, the local dose
is 104 - 107 Gy. In this case the radio toxicity from
Auger electrons is caused by 90% by indirect mecha-
nisms [6]. The high specific losses of α-particles allow
of effective use of 211At and 212Bi for treatment in
medicine. For example, for α-particles of these iso-
topes the radiation effect on a cell reaches the value of
1200. Therefore, a high-efficiency radiation effect will
be realized by means of introduction of these isotopes
into the tumor cell [7]. Practically all the antineo-
plastic pharmaceuticals used in the oncology practice
have a strong toxicity that menaces the patient life.
This feature of antineoplastic pharmaceuticals stimu-
lates the search for new modifications of pharmaceu-
ticals. The use of radiations with high deceleration
losses permits to realize a synergetic bystander effect
too [8-11]. This effect, a high density of deceleration
losses, cytotoxic effect and apoptosis can be reached
by application of radioactive cisplatin. Therefore, to-
day a necessity of carrying out the research on pro-
duction and use of radioactive cisplatin is an urgent
question. The combined influence of all the above-
mentioned factors will allow considerable decreasing
of cisplatin dose and, consequently, decreasing of the
toxic cisplatin influence in the course of medical treat-
ment of cancer carriers. With the purely radioactive
cisplatin the dose can be decreased by a factor of 10
and more. Note that the influence of radioactive cis-
platin is possible in the form of transplatin and in
other forms penetrating in the nucleus of a cell.
∗Corresponding author. E-mail address: dikiy@kipt.kharkov.ua
118 PROBLEMS OF ATOMIC SCIENCE AND TECHNOLOGY, 2007, N5.
Series: Nuclear Physics Investigations (48), p.118-121.
The aim of work is to develop a method for pro-
duction of radioactive cisplatin with the help of pow-
erful electron accelerators and to test the obtained
substance at biological objects.
2. PROCEDURE OF 195mPt EXTRACTION
AND CISPLATIN SYNTHESIS
The use of a powerful accelerators of NSC KIPT
for irradiation of platinum by electrons (200 µA,
50 MeV) permits to reach the total specific ac-
tivity of 195mPt and 193mPt 7 mCi/mg. The
195m,193mPt yield in the reactions 196Pt(γ,n)195mPt
and 194Pt(γ,n)193mPt was calculated with the help
of the program PENELOPE (Fig.) [12]. Such a
specific activity in many cases is insufficient for the
effective application in medicine practice. The spe-
cific activities of 195mPt to 10 Ci/mg are realized
by the 199Hg(γ,α)195mPt reaction. The separation
of 195mPt from mercury has been accomplished us-
ing the electrolysis. The yield of 195mPt in reaction
199Hg(γ,α)195mPt at a current of 200 µA and energy
26 MeV from the Hg target having a natural isotope
composition is about 30 mCi/day.
The cyclotron CV28 allows production of higher
specific activity of 195mPt by the 192Os(α,n)195mPt
reaction. At a current of 20 µA and en-
ergy 28 MeV the yield of 195mPt from the Os
target having a natural isotope composition is
1 mCi/day [13]. Such yield is smaller than yield
of 195mPt obtained by the method with the use
of the bremsstrahlung from electron accelerators.
30 35 40 45 50
1
2
3
4
5
6
7
0 2 4 6 8 10
0
2
4
6
8
10
To
ta
l s
pe
ci
fic
a
ct
iv
ity
19
3m
,1
95
m
P
t,
m
C
i/m
g
Electron energy, MeV
1x1
1x2
2x1
2x2
Specific activity at saturation of different targets as
a function of electron energy (beam current 200 µA,
diameter of beam 5 mm). Symbols - cylindrical
targets (diameter × height, cm)
We carried out the experiments of separation of
platinum isotope of 195mPt which was obtained in
the 197Au(γ,np)195mPt reaction. The 195mPt spe-
cific activity of 1 Ci/mg are obtained by means of
the 197Au(γ,np)195mPt reaction for electron energy
of 34 MeV and current of 200 µA. The sample of 1g
of gold (99.9%) was used as a target. The technology
of 195mPt separation from the gold target was de-
veloped. The procedure by this technology included
the process of gold target dissolution by boiling (Au,
HCl and HNO3 1:3). After dissolving the metal tar-
get, the HNO3 excess should be removed by gradual
addition of 10% HCl solution in the amount sufficient
to obtain the solution with an acid concentration of
3N.
For 195mPt extraction we used the extractor of
Kucher-Shtoll type designed for extraction by light
solvents. Then the round-bottomed flask was filled
with the prepared solution and the ethyl acetate
CH3COOC2H5 was gradually added up to the total
volume of 100 ml. The extraction process was car-
ried out by slow boiling. The total extraction time
was 5 hours. After that the platinum chloride was
cooled and 30 ml of ethyl acetate were reextracted.
This procedure was repeated three times. After reex-
traction the solution was poured into the separating
funnel where it was held during 2−3 min. Then the
solution was mixed by a magnetic stirrer during 5
min. To establish equilibrium the solution was kept
in rest.
The radioactivity of platinum chloride solution
was measured by the Ge(Li)-detector (50 cm3) with
the energy resolution of 2.2 keV for the line of
1333 keV. The spectrum contained 82.5% of Pt and
17.5% of Au. In addition to these elements there was
126I in the spectra.
In the next procedure by this technology to the
platinum-hydrochloride acid solution diluted in the
10 fold water amount we added a freshly prepared
25% potassium chloride solution for the full comple-
tion of precipitation. A yellow crystalline precipitate
K2PtCl6 was deposited. The precipitate was filtered
in 1.5−2 hours after deposition. The obtained pre-
cipitate of potassium chloroplatinite was flooded with
water (10-fold weight amount) and heated to boiling.
The boiling mixture was gradually filled up with lit-
tle portions of 1% oxalic salt K2C2O4. The solution
was evaporated in the water-bath until the crystal-
lization onset and then it was cooled at room tem-
perature. The solution of potassium chloroplatinite
K2[PtCl4] was mixed with the 20% solution of am-
monium acetate CH3COONH4 and heated to boil-
ing. After cooling Peyrone’s salt (NH3Cl)2Pt was
separated. The admixture of 196Au activity in syn-
thesized cisplatin was 1.4% relatively of the 195mPt
activity.
3. BIOLOGICAL TESTS
The cisplatin molecule containing 195mPt could
have an exceptional therapeutic use. Therefore, it is
important to possess information and reliable evalua-
tion of absorbed doses for different organs and tissues
in order to calculate subsequently the effective doses
for patients which will take 195mPt-cisplatin.
The experiment was made on animals (male white
mice, weighing 18 g). Radioactive cisplatin in the
dose of 13 kBq was introduced into animals intraperi-
toneally. The absorbed doses to animal from 195mPt
(mGy/MBq) was measured in different organs (kid-
neys, liver, spleen, bowels, testicles, wall of urinary
119
bladder, skin). The organs from 10 animals to be
studied were weighed and placed in an aluminums
container which was installed on the Ge(Li)- detec-
tor for registration of the absorbed dose.
The results obtained demonstrated that the high-
est 195mPt-cisplatin absorption dose is registered in
the liver (0.72±0.23), kidneys (0.40±0.07), testicles
(0.55±0.15), spleen (0.35±0.05), wall of urinary blad-
der (0.25±0.02); skin (0.21±0.04) mGy/MBq. The
experiments were carried out to study the influence of
initial and radioactive cisplatin on a cell suspension
of adenocarcenoma of Ehrlich. The cell concentra-
tion was 1.8·106 cells/ml. The cell viability was de-
termined by the method of supravital staining. The
introduced dose of the initial cisplatin was 7.5 µg/ml,
of the radioactive cisplatin it was 0.017 pg/ml. Into
every sample we introduced 0.03 ml of penicillin (180
units) and 0.03 mg of sulfanilamide (300 µg). The
samples were held in the thermostat at a temperature
of 37◦C for incubation. The tumor cell size was mea-
sured by means of a polarization microscope (×200)
and was 0.015 mm before introduction of cytostatic
agents. After 12 hours of incubation with the initial
cisplatin the cell size was 0.010−0.015 mm, with the
radioactive cisplatin it was 0.005−0.007 mm.
A series of experiments were carried out to study
the effect of untreated and radioactive cisplatin on
the growth of a solid tumor in mousses. To estimate
the effect of introduced radioactive drugs on the tu-
mor growth we defined the rate of its growth inhibi-
tion (D%) calculated by the formula:
D = ((V0 − V1)/V0) · 100,
where V0 is the tumor volume in the control animals,
V1 is the tumor volume in the animals which received
untreated and radioactive cisplatin.
The studies were carried on male mousses of 18 g
weight bred at the Kharkiv Academy of Pharmacol-
ogy. A slurry of ascetic cells of the Ehrich’s ade-
nocarcinoma received from the Institute of Cryobiol-
ogy and Cryomedicine was used as a tumor model.
The slurry of cells (106 cells/ml) was inoculated into
the right thigh region of mousses. There were three
groups of animals: group I - animals-tumor carriers
(10 mousses); group II - animals selected for intro-
duction of untreated cisplatin (15 mousses); group
III - animals-tumor carriers selected for introduction
of radioactive cisplatin (15 mousses).
Every day the animals have been examined,
weighted, fed by the ration; coops were daily cleaned.
Since 11 day after tumor subinoculation every other
day we introduced untreated cisplatin into the ani-
mals from group II (introperitonial introduction by
the dose of 0.8 mg per kg of the animal’s weight).
In total 5 injections were made. The animals from
group II received 0.5 ml of injection water by the
same scheme. The animals from group III received
only one dose (6.5 kBk per 15 g) of radioactive cis-
platin.
In 21 day after tumor subinoculation we have
measured the physiologic indices of animals (total
weight (g), weights of the spleen (mg), thymus (mg),
tumor (mg)), as well as, some hematological indices.
We have noticed the decrease of the animals’ weight
and the tumor growth inhibition in the animals of
group II and group III. The rate of tumor growth in-
hibition, as a result of radioactive cisplatin introduc-
tion, was 65% that is significantly higher than the
rate of tumor growth inhibition caused by the action
of untreated cisplatin (32.5%). The results obtained
give hope for the advanced use of radioactive cisplatin
in the oncological practice.
4. CONCLUSIONS
1. The method of production 195mPt with high
specific activity by means of an irradiation of a gold
target by bremsstrahlung of the electronic accelerator
has been developed.
2. The method of separation of 195mPt by means
of extraction of gold has been developed and realized.
3. Synthesis of radioactive cisplatin has been de-
veloped.
4. Test of radioactive cisplatin on experimental
animals has been carried out. High efficiency of ra-
dioactive cisplatin for treatment of cancer tumors of
animals has been received.
This work was supported by STCU, project
No.1768.
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ПРОТИВООПУХОЛЕВАЯ ТЕРАПИЯ РАДИОАКТИВНЫМ
ЦИСПЛАТИНОМ В ЭКСПЕРИМЕНТЕ
Н.П. Дикий, А.Н. Довбня, Ю.В. Ляшко, Е.П. Медведева, Д.В. Медведев, В.Л. Уваров
Рассматриваются способы производства 195mPt на линейных ускорителях электронов и циклотроне
ННЦ ХФТИ. Разработаны методы выделения 195mPt из облученных образцов. Реализованы методы
синтеза цисплатина с использованием радиоактивного изотопа 195mPt. Приведены результаты биоло-
гических испытаний радиоактивного цисплатина на животных. Наши предварительные результаты
демонстрируют возможность использования радиоактивного цисплатина для лечения канцерогенных
заболеваний.
ПРОТИПУХЛИННА ТЕРАПIЯ РАДIОАКТИВНИМ
ЦИСПЛАТИНОМ В ЕКСПЕРИМЕНТI
М.П. Дикий, А.М. Довбня, Ю.В. Ляшко, О.П. Медведєва, Д.В. Медведєв, В.Л. Уваров
Розглядаються способи виробництва 195mPt на лiнiйних прискорювачах електронiв i циклотронi
ННЦ ХФТI. Розроблено методи видiлення 195mPt з опромiнених зразкiв. Реалiзовано методи синтезу
цисплатину з використанням радiоактивного iзотопу 195mPt. Наведено результати бiологiчних випро-
бувань радiоактивного цисплатину на тваринах. Нашi попереднi результати демонструють можливiсть
використання радiоактивного цисплатину для лiкування канцерогенних захворювань.
121
|
| id | nasplib_isofts_kiev_ua-123456789-110402 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1562-6016 |
| language | English |
| last_indexed | 2025-12-02T09:45:09Z |
| publishDate | 2007 |
| publisher | Національний науковий центр «Харківський фізико-технічний інститут» НАН України |
| record_format | dspace |
| spelling | Dikiy, N.P. Dovbnya, A.N. Lyashko, Y.V. Medvedeva, E.P. Medvedev, D.V. Uvarov, V.L. 2017-01-04T11:39:31Z 2017-01-04T11:39:31Z 2007 Antineoplastic therapy by radioactive cisplatin in experiment / N.P. Dikiy, A.N. Dovbnya, Y.V. Lyashko, E.P. Medvedeva, D.V. Medvedev, V.L. Uvarov // Вопросы атомной науки и техники. — 2007. — № 5. — С. 118-121. — Бібліогр.: 13 назв. — англ. 1562-6016 PACS: 29.17.+w, 28.41.Kw https://nasplib.isofts.kiev.ua/handle/123456789/110402 The method of ¹⁹⁵mPt production on linear electron accelerators and cyclotron of NSC KIPT are described. The method of ¹⁹⁵mPt separation from the irradiated samples are developed. The methods of cisplatin synthesis with use of a radioactive isotope of ¹⁹⁵mPt are realized. Results of biological tests of radioactive cisplatin on animals are described. Our preliminary results demonstrate the feasibility of radioactive cisplatin for treatment of cancer diseases. Розглядаються способи виробництва ¹⁹⁵mPt на лінійних прискорювачах електронів і циклотроні ННЦ ХФТІ. Розроблено методи виділення ¹⁹⁵mPt з опромінених зразків. Реалізовано методи синтезу цисплатину з використанням радіоактивного ізотопу ¹⁹⁵mPt. Наведено результати біологічних випробувань радіоактивного цисплатину на тваринах. Наші попередні результати демонструють можливість використання радіоактивного цисплатину для лікування канцерогенних захворювань. Рассматриваются способы производства ¹⁹⁵mPt на линейных ускорителях электронов и циклотроне ННЦ ХФТИ. Разработаны методы выделения ¹⁹⁵mPt из облученных образцов. Реализованы методы синтеза цисплатина с использованием радиоактивного изотопа ¹⁹⁵mPt. Приведены результаты биологических испытаний радиоактивного цисплатина на животных. Наши предварительные результаты демонстрируют возможность использования радиоактивного цисплатина для лечения канцерогенных заболеваний. This work was supported by STCU, project No.1768 en Національний науковий центр «Харківський фізико-технічний інститут» НАН України Вопросы атомной науки и техники Ядернo-физические методы и обработка данных Antineoplastic therapy by radioactive cisplatin in experiment Протипухлинна терапія радіоактивним цисплатином в експерименті Противоопухолевая терапия радиоактивным цисплатином в эксперименте Article published earlier |
| spellingShingle | Antineoplastic therapy by radioactive cisplatin in experiment Dikiy, N.P. Dovbnya, A.N. Lyashko, Y.V. Medvedeva, E.P. Medvedev, D.V. Uvarov, V.L. Ядернo-физические методы и обработка данных |
| title | Antineoplastic therapy by radioactive cisplatin in experiment |
| title_alt | Протипухлинна терапія радіоактивним цисплатином в експерименті Противоопухолевая терапия радиоактивным цисплатином в эксперименте |
| title_full | Antineoplastic therapy by radioactive cisplatin in experiment |
| title_fullStr | Antineoplastic therapy by radioactive cisplatin in experiment |
| title_full_unstemmed | Antineoplastic therapy by radioactive cisplatin in experiment |
| title_short | Antineoplastic therapy by radioactive cisplatin in experiment |
| title_sort | antineoplastic therapy by radioactive cisplatin in experiment |
| topic | Ядернo-физические методы и обработка данных |
| topic_facet | Ядернo-физические методы и обработка данных |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/110402 |
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