Enterosorption as a method to decrease the systemic toxicity of cisplatin
A perspective adsorptive method to minimize systemic toxic effects of chemotherapy is enterosorption (ES). However, the capabilities of this method are far from being completely studied. The question remains opened — should ES be initiated in the first hours on completing cytostatic infusion without...
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| Опубліковано в: : | Experimental Oncology |
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| Дата: | 2013 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2013
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| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Цитувати: | Enterosorption as a method to decrease the systemic toxicity of cisplatin / L.A. Sakhno, O.V. Yurchenko, V.N. Maslenniy, K.I. Bardakhivskaya, V.V. Nikolaeva, A.A. Ivanyuk, O.O. Shevchuk, V.G. Korotich, V.G. Nikolaev // Experimental Oncology. — 2013. — Т. 35, № 1. — С. 45-52. — Бібліогр.: 28 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859602436788846592 |
|---|---|
| author | Sakhno, L.A. Yurchenko, O.V. Maslenniy, V.N. Bardakhivskaya, K.I. Nikolaeva, V.V. Ivanyuk, A.A. Shevchuk, O.O. Korotich, V.G. Nikolaev, V.G. |
| author_facet | Sakhno, L.A. Yurchenko, O.V. Maslenniy, V.N. Bardakhivskaya, K.I. Nikolaeva, V.V. Ivanyuk, A.A. Shevchuk, O.O. Korotich, V.G. Nikolaev, V.G. |
| citation_txt | Enterosorption as a method to decrease the systemic toxicity of cisplatin / L.A. Sakhno, O.V. Yurchenko, V.N. Maslenniy, K.I. Bardakhivskaya, V.V. Nikolaeva, A.A. Ivanyuk, O.O. Shevchuk, V.G. Korotich, V.G. Nikolaev // Experimental Oncology. — 2013. — Т. 35, № 1. — С. 45-52. — Бібліогр.: 28 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | A perspective adsorptive method to minimize systemic toxic effects of chemotherapy is enterosorption (ES). However, the capabilities of this method are far from being completely studied. The question remains opened — should ES be initiated in the first hours on completing cytostatic infusion without the risk of their anticancer activity to be decreased. Aim: to analyze ES influence on anticancer activity and toxic reactions of cisplatin (CP) upon the use of carbon enterosorbent in 1 h after intravenous administration of cytostatic. Methods: CP at the dose of 1 mg/kg body weigh (BW) was administered to Guerin carcinoma-bearing rats each second day for two weeks. Enterosorbents on the basis of highly activated carbon fibers were administered by per os daily 1 h after CP injection. 3 days after the last CP administration the rats were weighted and blood under ether narcosis has been taken for biochemical examination. Tumors and innate organs were isolated, weighted, and fixed in 4% buffered formalin for morphologic examination. Results: In rats administered with CP at the background of ES, BW loss was in 1.6 times lower than in animals after CP session. Relative kidney weight in CP-treated rats was 33.9% higher than in normal ones (p ≤ 0.05). No significant differences were detected between relative kidney weights in the CP + ES-treated and intact animals. Introduction of ES allowed prevent an 30% increase of creatinin content observed in blood plasma after CP treatment (р ≤ 0.05). Urea content was 1.7 times lower in blood plasma of CP + ES-treated rats than after CP treatment. CP caused significant toxic injuries in kidneys, liver, and spleen tissues. Morphologic structure of organs in rats treated with CP at the background of ES was affected at much lower degree. In tumors, large areas of newly formed connective tissue and blood vessels have been fixed after the CP+ES action instead of large necrotic area observed after CP treatment. ES caused insignificant suppression of Guerin carcinoma growth and had additional impact to inhibitory action of CP. Conclusion: Active carbon enterosorbents which are administrated just 1 h after CP administration possesses detoxicating potential sufficient for significant elimination of toxic effect of the cytostatic at the background of complete preservation of its antitumor activity.
|
| first_indexed | 2025-11-28T00:00:03Z |
| format | Article |
| fulltext |
Experimental Oncology 35, 45–52, 2013 (March) 45
ENTEROSORPTION AS A METHOD TO DECREASE THE SYSTEMIC
TOXICITY OF CISPLATIN
L.А. Sakhno1,*, O.V. Yurchenko1, V.N. Maslenniy1, K.I. Bardakhivskaya1, V.V. Nikolaeva1,
A.A. Ivanyuk1, O.O. Shevchuk2, V.G. Korotich1, V.G. Nikolaev1
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of NAS of Ukraine, Kyiv
03022, Ukraine
2I.Ya. Horbachevsky State Medical University, Ternopil 46001, Ukraine
A perspective adsorptive method to minimize systemic toxic effects of chemotherapy is enterosorption (ES). However, the capa-
bilities of this method are far from being completely studied. The question remains opened — should ES be initiated in the first
hours on completing cytostatic infusion without the risk of their anticancer activity to be decreased. Aim: to analyze ES influence
on anticancer activity and toxic reactions of cisplatin (CP) upon the use of carbon enterosorbent in 1 h after intravenous adminis-
tration of cytostatic. Methods: CP at the dose of 1 mg/kg body weigh (BW) was administered to Guerin carcinoma-bearing rats
each second day for two weeks. Enterosorbents on the basis of highly activated carbon fibers were administered by per os daily
1 h after CP injection. 3 days after the last CP administration the rats were weighted and blood under ether narcosis has been
taken for biochemical examination. Tumors and innate organs were isolated, weighted, and fixed in 4% buffered formalin for
morphologic examination. Results: In rats administered with CP at the background of ES, BW loss was in 1.6 times lower than
in animals after CP session. Relative kidney weight in CP-treated rats was 33.9% higher than in normal ones (p ≤ 0.05). No sig-
nificant differences were detected between relative kidney weights in the CP + ES-treated and intact animals. Introduction of ES al-
lowed prevent an 30% increase of creatinin content observed in blood plasma after CP treatment (р ≤ 0.05). Urea content was
1.7 times lower in blood plasma of CP + ES-treated rats than after CP treatment. CP caused significant toxic injuries in kidneys,
liver, and spleen tissues. Morphologic structure of organs in rats treated with CP at the background of ES was affected at much
lower degree. In tumors, large areas of newly formed connective tissue and blood vessels have been fixed after the CP+ES action
instead of large necrotic area observed after CP treatment. ES caused insignificant suppression of Guerin carcinoma growth and
had additional impact to inhibitory action of CP. Conclusion: Active carbon enterosorbents which are administrated just 1 h after
CP administration possesses detoxicating potential sufficient for significant elimination of toxic effect of the cytostatic at the
background of complete preservation of its antitumor activity.
Key Words: enterosorption, activated carbon fibrous sorbents, cisplatin, chemotherapy.
The search for way to minimize systemic toxic effects
of chemotherapy without the decrease of its anticancer
activity is still actual. A special place in this problem
solving is occupied by the methods of sorption therapy
the possibilities of which are being constantly expanded
due to the development of new effective sorbents of me-
dicinal purposes and original approaches for their use.
After massive chemotherapy accompanied with
an expressed endogenous intoxication syndrome and
cytostatic-dependent myelodepression, the method
of hemosorption (HS) allows significantly alleviate
these complications and thereby provide the possibility
to continue the therapy by radical schemes [1]. In such
situations the use of Hemosorbents Granulated Deli-
ganding (HSGD) developed in R.E. Kavetsky Institute
of Experimental Pathology, Oncology and Radiobio-
logy of NAS of Ukraine (IEPOR) for effective removal
of hydrophobic toxic metabolites strongly bound with
blood plasma proteins (nonconjugated bilirubin, free
fatty acids, phenols, bile acids, mercaptanes, a number
of uraemic toxins) during HS procedure allows achieve
qualitatively new therapeutic effects related to deep pu-
rification of transport proteins and blood cell membranes
in patients with myocarditis, hepatitis and renal failure
caused by cytostatic therapy [2, 3].
HS method provides unique possibilities for control
of local and systemic pharmacokinetics of anticancer
preparations. Therapeutically significant differences
between the concentrations of anticancer prepara-
tions in the tumor and the most vulnerable organs are
achieved in the first variant via selective intraarterial
administration of high doses of cytostatics with the
following sorption purification of blood which outflows
from an affected organ [4–7].
Sorption system on the basis of highly active hemo-
sorbents of HSGD type performs deep blood purifica-
tion from protein bound compounds including the large
majority of anticancer preparations, and is capable
to provide a safe sorption barrier that limits anticancer
agent entering into systemic circulation. Thus, such
approach allows regional introduction of high doses
of cytostatics into the tumor with the decreased risk
of systemic toxic effects. To increase the efficacy
of removal from blood of cisplatin (CP) excess during
the control of its local pharmacokinetics, one would
sequentially introduce sorption column and dialyza-
tor into extracorporeal circuit [8]. The other method
proposed is related to the control of systemic pharma-
cokinetics and make unneedful the collection of blood
enriched with chemopreparation excess directly from
Received: February 8, 2013.
*Correspondence: E-mail: lsakhno7@gmail.com
Abbreviations used: ACFS — activated carbon fibrous sorbents;
CP — cisplatin; ES — enterosorption; HS — hemosorption; HSGD —
Hemosorbent Granulated Deliganding; BW — body weight.
Exp Oncol 2013
35, 1, 45–52
46 Experimental Oncology 35, 45–52, 2013 (March)
venous collectors of separate organ or tumor lesion, into
which intraarterial catheter for cytostatic administra-
tion is applied. Instead of this blood is taken with high
speed (from 500 ml/min to 1 ml/min and more) from
any appropriate vasculature point and is returned into
systemic circulation after massive sorption purification
providing removal not less than 95% of chemoprepara-
tion. This variant also allows provide effective defence
of vital organs from the action of high doses of cytostatic
drugs [9]. One should mention that local scheme as well
could provide the control of systemic pharmacokinetics
of anticancer preparation, however just in a case when
its concentration on column entry is lower that sys-
temic concentration supported by incomplete isolation
of regional circle. In both mentioned cases the action
of HS is not limited by its effect on the local and systemic
concentration of anticancer drugs the large majority
of which are related to radiomimetics, i.e., chemical
compounds simulating the action of penetrating radia-
tion. That’s why it is reasonable to mention our previous
results on the use of hemocarboperfusion method
in a treatment of acute radiation sickness; then blood
purification in dogs at the terms of 2 to 24 h after their
homogenous irradiation at minimal absolutely lethal
dose of 5.25 Gy has allowed achieve 65–70% animal
survival at the background of an expressed myelopro-
tective effect [10]. It could not be excluded that such
effect of HS could be true also for cytostatic therapy
as far as for anticancer cytostatic pharmacokinetic con-
trol, but sorption purification of blood is performed not
after accomplished radiation injury as in a case of early
treatment of acute radiation sickness, but strictly during
the primary action of radiomimetic agent.
As a perspective method to fight endotoxicosis
caused by systemic toxicity of anticancer cytostatics,
one could consider enterosorption (ES), which efficacy
has been initially proven by the results of experimental
studies with the use of animals bearing transplanted
tumors [11–13].
In the frame of study of ES effect toward myelotoxic-
ity of anticancer preparations, there have been shown
that ES performed in Guerin carcinoma-bearing rats
after treatment with cyclophosphamide and methotrex-
ate, has demonstrated an expressed myeloprotective
effect toward all main bone marrow cell elements [13].
In Shvets erythromyelosis-bearing rats treated with
carminomycine the myelocaryocyte and peripheral
granulocyte counts were two and three times lower,
respectively, that these in animals that were treated
with carbon enterosorbents after antibiotic treatment
[13]. Along with this ES alone demonstrates insig-
nificant suppressing effect toward transplanted tumor
growth and elongates life time of animals treated with
cytostatics compared to animals which are not treated
with ES. In patients with Hodgkin’s lymphoma two-week
ES course after intense chemoradiotherapy allowed
reduce leukopenia duration by 1.5 times [14].
ES efficacy has been successfully applied in pa-
tients with malignant breast tumors and large bowel
cancer at the post-operative period [15]. Two-weeks
administration of carbon-mineral sorbent SCMS-1 with
immobilized metronidazole which has been initiated
a day after beginning of chemotherapy course, pre-
vented the development of expressed leukopenia and
thrombocytopenia, elevation of urea and bilirubin con-
tents, aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) levels in blood plasma, and
also decreased an intensity of clinical intoxication
symptoms — nausea and vomiting.
An important step in ES development was done
by creation of moist boluses or granules formed from
carbon fibers or micronized carbon particles with the
use of water as a binder (Carboline, IEPOR production,
Ukraine). Such technology provides total preservation
of adsorptive properties of the sorbent and improves
the kinetic parameters of adsorption. Also, the washed
down preparation is immediately dispersed in oral cavity
and is swallowed easily what is of special importance
in the patients with increased vomiting activity. An ef-
ficacy of the use of carbon enterosorbent Carboline for
prophylaxis of acute and delayed emetogenic toxicity
of cytostatics has been demonstrated in patients with
breast and lung cancer and Hodgkin’s disease [16].
Carboline at the dose of 15 tablets daily for 5 days before
and 5 days after polychemotherapy session (ES is not
indicated at the day of cytostatic administration) allows
prevent severe toxic reactions caused by polychemo-
therapy which includes platinum group preparations,
and by 4 times increases the number of patients without
toxic reaction caused by platinate-free polychemo-
therapy. Delayed emetogenic toxicity characteristic
nearly for half of the patients, has been observed just
in 5% of the patients treated with ES.
So, the results of experimental studies and the
data of clinical observations support an expediency
of ES introduction into the complex of measures di-
rected on prophylaxis and minimization of systemic
toxic effects of anticancer preparations. However, the
capabilities of this method are far from being completely
studied yet. In particular, the question remains — should
ES be initiated in the first hours on completing cytostatic
perfusion without the risk of decreasing the anticancer
activity of the preparation. Therefore, the task of our
experimental studies was to analyze ES influence on an-
ticancer activity of CP and toxic reactions upon the use
of carbon enterosorbent in 1 h after intravenous admin-
istration of cytostatic characterized by quick clearance
from blood via glomerular excretion [17]. According
to our earlier results (unpublished data), CP concen-
tration in blood serum of Guerin carcinoma-bearing
rats 5 min after intravenous administration of CP was
equal to 24.5% of injected dose and was not higher
than 3 and 0.9% in 1 and 24 h respectively. Such phar-
macokinetics of the cytostatic has been described for
athymic mice bearing subcutaneous A2780 cell ovarian
xenografts [18].
MATERIALS AND METHODS
Animals and experimental design. The stu-
dies were carried out on white inbred rats weighting
Experimental Oncology 35, 45–52, 2013 (March) 47
200 ± 20 g from the IEPOR vivarium. All animals pro-
cedures were carried out according to the rules and
requirements of local Ethic Committee of IEPOR. Guerin
carcinoma Т8 was transplanted subcutaneously in the
left femur of animals. When tumor volume reached ap-
proximately 0.5 cm3 animals were randomly distributed
according to their tumor volume into 4 groups: 1 —
intact Guerin carcinoma-bearing rats (tumor) (n = 7);
2 — Guerin carcinoma-bearing rats treated with ES
(tumor + ES) (n = 8); 3 — with CP (tumor + CP) (n = 8);
and 4 — with CP and ES (tumor + CP + ES) (n = 8).
Control group consisted of 6 normal rats.
CP (Veropharm, Russia) has been injected each al-
ternate day in tail vein at the dose of 1.0 mg/1 kg body
weight (BW) for 2 weeks.
As enterosorbent, Carboline on the basis of highly
activated fibrous carbon materials (Ukraine) was used.
The fibers at the quantity of 0.65 g/1 kg BW as a sus-
pension in 2 ml of distilled water were introduced with
the use of tube into rat stomach 1 h after CP adminis-
tration. Rats treated with CP only were introduced with
2 ml of distilled water without the sorbent. Animals
treated with enterosorbents received 0.5 ml of physi-
ologic solution instead of CP.
Tumor volume was determined by three orthogonal
diameters (а, b, c) according to the prolate ellipsoid
formula: V = 0.52 (a×b×c). To characterize the dynamic
tumor growth we have used K coefficient determined
as the ratio between tumor volume at the given moment
and tumor volume at the moment of the first CP injection.
Three days after the last administration of the
preparations the rats were weighted and blood under
ether narcosis has been taken from vena cava inferior.
Tumors and innate organs (lever, kidney, spleens)
were isolated, washed with cold physiologic solution,
weighted, and fixed in 4% buffered formalin.
The loss of BW was calculated using the following
formula: BW loss (%) = (BW at the 1st day of CP in-
jection — BW at the 3rd day after last CP injection)
x100/ BW at the first day of CP injection.
Plasma concentrations of creatinin, urea, urinary
acid, AST and ALT were analyzed at the clinical labora-
tory using a Clinical System (Beckman, CA).
The statistical significance of the differences
between mean values was assessed by the Stu-
dent’s t-test.
Morphology examination. Fixed in formalin
tissues of organs and tumors were sectioned, de-
hydrated in 70% ethanol and paraffin embedded
according to routine technique. Serial 5 μm sections
were stained with hematoxylin and eosin, examined
by light microscopy.
RESULTS AND DISCUSSION
The main task of our study was to analyze ES ef-
fects toward systemic toxic CP reactions in Guerin
carcinoma beagin rats treated with enterosorbent
1 h after intravenous administration of the cytostatic.
The decrease of animal BW could serve as an indica-
tive criterion of endotoxicosis caused by toxic effects
of the cytostatic and in part — by tumor growth [19].
Before CP administration, the Guerin carcinoma-
bearing rat BW was recorded. No significant differences
were detected between the intact tumor, tumor+ES,
tumor+CP, tumor+CP+ES groups: 249.8±22.4;
246.2±19.4; 254.4±19.0; 242.6±14.1 g respectively.
In the process of tumor development animal BW in intact
tumor group decreased by 9.4±4.1% versus 7.4±3.6%
in tumor+ES group (Table 1). After CP session the animal
BW loss was 13.1±8.7%. Introduction of ES allowed de-
crease BW loss by 1.6 times. In tumour-bearing animals
there has been recorded insignificant elevation of rela-
tive kidney weight (total organ weight/BW) while in rats
treated with CP this index was 33.9% (p≤0.05) higher
than in normal animals. In rats treated with CP+ES rela-
tive kidney weight didn’t differ significantly from respec-
tive value in control group. An increase of relative kidney
weight by 1.5 times along with alterations in some bio-
chemical indexes and glomerular and tubular disruption
has been observed in Guerin carcinoma-bearing rats
upon single intraperitoneal administration of CP at the
dose of 8 mg/kg [20]. Kidney hypertrophy is among
manifestations of compensatory reaction in response
to nephrotoxic agent action and is caused by adaptive
increase of the size of remaining functional nephrones
in which filtration rate and reabsorption of water-soluble
compounds is being increased [21].
Table 1. Influence of ES on toxic reactions caused by Guerin carcinoma
growth and cisplatin administration
Index
Groups
Normal
rats
Guerin carcinoma-bearing rats
Intact ES CP CP + ES
BW loss, % 9.4±4.1 7.4±3.6 13.1±8.7 8.3±3.7
Kidney weight/BW 6.2±1.3 6.8±0.8 6.3±0.7 8.3±1.7* 7.8±1.0
Liver weight /BW 44,0±5.1 51.2±8.2 44.5±6.3 48.7±3.1 43.8±6.2
Spleen weight/BW 5.8±1.0 9.5±2.9 9.3±1.7 5.0±0.9 4.2±0.7
Blood plasma creat-
inin content, mMol/l
61.9±5.7 71.0±9.7 58.4±11 80.3±9.0* 67.7±9.2
Blood plasma uric
acid content, mMol/l
118±17.8 114±15.6 122±10.4 102±11.9 85±7.9
Blood plasma urea
content, mMol/l
8.9±1.1 9.3±0.9 10.4±1.2 11.7±1.6 10.5±1.2
Blood plasma ALT, U/l 65±17 64±11 61±9 76±13 59±11
Blood plasma AST, U/l 135±19 - - 212±16* 143±18
* Difference is significant compared to the normal rats (p ≤ 0.050).
After CP treatment insignificant increase of relative
weights of liver and spleen in tumor + CP and tumor +
CP + ES groups has been registered (Table 1), and
more expressed one — in intact Guerin carcinoma-
bearing rats. ES has been causing normalizing effect
on relative liver weight, but had no effect on spleen
hyperplasia (tumor + ES group).
Blood plasma level of creatinin is a standard
marker of glomerular disruption [20, 21]. Creatinin
content which was practically equal in blood plasma
of tumor-bearing rats and intact animals, has been
elevated by 30% after CP session (р ≤ 0.05). Introduc-
tion of ES allowed prevent an increase of this index.
After CP session there has been registered an elevation
of urea content in blood plasma by 31%, while after
combined treatment with CP + ES — by 17.9%. Uric acid
content in blood plasma of rats from these groups stood
within values of intact animals. AST level in rats treated
48 Experimental Oncology 35, 45–52, 2013 (March)
with CP was higher by 1.4 fold, and in animals treated
with CP+ES was equal to that in intact control. No sig-
nificant differences in ALT levels have been recorded.
The observed tendencies evidencing on modifying
effect of ES on systemic CP toxicity, have found new
confirmation during comparative analysis of alterations
of histological structure of innate organs of rats upon
tumour growth and CP or CP + ES treatment.
Morphological study of liver tissues of Guerin
carcinoma-bearing rats has revealed the disruption
of beam structure and dystrophy of hepatocytes,
increased number of Kupffer cells and their sizes,
and the presence of phagocytized cell debris in their
cytoplasm (Fig. 1 a). Enlargement of sinusoids and ac-
cumulation of erythrocytes inside them could evidence
on toxic effect of growing tumor on cell membranes
of hepatocytes and endothelial cells. In kidney tis-
sue there has been observed an expressed tubular
cell dystrophy, formation of lumen and decreased
cell element numbers in glomerulus which in some
glomerulus are represented just by ‘naked’ nuclei
(Fig. 1 b). In the majority of glomerulus one could
observe haemorrhages of various degree, in tubular
lumen — small lesions of haemorrhages and hyaline
inclusions. Morphological structure of spleen was
characterized by increased number of lymphoid fol-
licles, some of them contained secondary germinal
centers with blast elements, and rarely — significant
amounts of macrophages (Fig. 1 c).
At the background of ES the morphological chan-
ges in innate organ structure caused by growing
tumour have been expressed at significantly lower
level (Figс. 2 a–c). In some animals the morphological
picture was close to normal one.
Upon CP action the degree of toxic damage of in-
nate organ tissues drastically decreased. Morphologic
structure of liver tissue is notably disrupted, large ne-
crosis area could be noticed. Hepatocytes are mostly
in necrobiosis state. The rest of them have patterns
of dystrophy (Fig. 3 a). Also, in liver cells there were
observed “naked” nuclei, cell shadows, and empty
cytoplasm. One could see small haemorrhages be-
tween hepatocyte cords and hyalinization of some
vessels. CP caused notable disruption in renal tissue
structure, alteration of anatomic region of glomerulus
location which contained lower numbers of functional
cells (Fig. 3 b). There have been recorded dystrophic
changes practically in all functional cell elements,
tubular necrosis, destruction of glomerules and forma-
tion of large lumens between tubules. In spleen tissue
there was observed the formation of large secondary
germinal centers, devastation of cells in marginal zone
of spleen, erythrocyte destruction in red pulpa with
appearance of small haemorrhages (Fig. 3 c).
Microscopic picture of innate organ tissues of rats
treated with CP and carbon enterosorbents is com-
pletely different: their morphological structure is af-
fected at significantly lower degree however, it varies
between some animals (Fig. 4 a–c).
In one rat liver structure is completely normal.
In other animals hepatocytes possessed the patterns
of dystrophy of different degree. However, in this cases
around vessels there has been detected an appear-
ance of hepatocytes possessing more basophilic cyto-
plasm and dense nucleus (so called dark hepatocytes)
which represent young liver cells that replace dead
ones; this fact points on improvement of functional
state of liver. In kidney tissues toxic disruption is ex-
pressed at lower level. There were no erythrocytes and
hae morrhages in glomerules, and high cellularity has
been registered. In tubular lumen there was detected
a
b
c
Fig. 1. Morphological structure of innate organs in Guerin
carcinoma-bearing rats (х 200): a — disruption of beam struc-
ture and dystrophy of hepatocytes in liver; b — haemorrhages
in glomerules and hyalinosis in renal tubules; c — secondary
germinal centers with blast elements in spleen
Experimental Oncology 35, 45–52, 2013 (March) 49
significantly lower numbers of erythrocytes, haemor-
rhages were rare enough. The large majority of cells
in tubules are of normal morphological structure, the
quantity of lumens between tubules and their sizes
were lower. In one animal kidney structure was practi-
cally equal to that in healthy rats. Characteristic pattern
of spleen was the prevalence of lymphoid follicles with
extended marginal zone over red pulpa.
Thus, daily administration of carbon enterosor-
bents results in significant suppression of systemic
toxic reactions of CP. The obtained result could
be of great practical importance, however, only in the
case if ES doesn’t influence anticancer effect of the
cytostatic. That’s why at the next stage of our research
we have analyzed this issue.
An analysis of Guerin carcinoma growth in the groups
of rats treated with the enterosorbent or CP alone
or in combination has shown that daily administration
of enterosorbent caused insignificant tumor growth
inhibition and insignificant enhancement of CP inhibiting
action (Fig. 5). On day 22 after tumor cell transplanta-
a
b
c
Fig. 2. Morphological structure of innate organs in Guerin
carcinoma-bearing rats after ES treatment (х 200): a — liver;
b — kidneys; c — spleen
a
b
c
Fig. 3. Morphological structure of innate organs in Guerin
carcinoma-bearing rats upon CP treatment: a — disruption
of liver tissue structure, regions of necrobiosis, appearance
of naked nuclei and empty cytoplasm (х200); b — dystrophy
of functional renal cell elements, tubular necrosis, glomerular
destruction and formation of large lumens between the tubules
(х200); c — devastation of cells in marginal zone of spleen,
erythrocyte destruction in red pulpa with appearance of moder-
ate haemorrhages (х100)
50 Experimental Oncology 35, 45–52, 2013 (March)
tion an average tumor weight in tumor-bearing rats
achieved 37.2 ± 9.5 g, in animals treated with entero-
sorbent — 27.2 ± 12.6 g, in animals treated with CP and
CP + ES — 1.6 ± 2.5 and 1.3 ± 1.6 g respectively. At this
day 2 from 7 tumor-bearing rats died, and 1 from 8 ani-
mals — in tumor + ES group. Tumor regression was not
observed in both groups. In groups treated with CP and
CP + ES none of animals died, while tumor absence was
observed in 1 and 2 animals respectively.
On day 22 morphological structure of tumor is typi-
cal for Guerin carcinoma (Fig. 6 a). In some tumors
small area of necrosis and the presence of dystro-
phy-like altered cells were detected. Administration
of enterosorbent did n’t significantly alter morphology
picture of tumor (Fig. 6 b). Upon CP action necrotic
regions of different sizes were formed in tumor tissue
which were large enough in some animals (Fig. 6 c).
Connective tissue is observed in moderate quantity
as an appearance of separately placed fibroblast-like
cells or their accumulations. ES introduction drastically
alters morphological structure of tumor. In tumor one
could observe large areas of newly generated con-
nective tissue which consists from connective fibers,
fibroblasts, macrophages and large number of newly
formed blood vessels (Fig. 6 d). In connective lining
there were detected single tumor cells and single small
regions of necrosis. Thus, instead of large necrotic area
observed in tumor after CP treatment, the combined
action of CP + ES resulted in the death of the majority
of tumor cells and in appearance of connective tissue
elements. The mechanisms and consequence of such
events require the performance of additional studies.
So, the obtained results have shown that potent an-
titoxic action of enterosorbents which are administrated
1 h after intravenous administration of CP, is realized
at the conditions of full preservation of its cytoxic activity.
It is known that CP possesses a dose-dependent neph-
rotoxicity which is characterized by cumulative charac-
ter and is the main toxic factor which limits its high-dose
regimen of use [22]. There is also a significant number
of works devoted to altered gene expression in kidney
tissue upon platinate action [22, 23]. The conditions
of ES performance selected by us had allowed to pre-
vent severe toxic damage of tissues of kidney and
other organs caused by toxic action of CP and tumor
growth. Among many mechanisms of ES multifactor
influence which have been discussed in a number of re-
lated studies [24–26], one should consider an evident
role of adsorption of toxic products generated in the
process of damage of normal and tumor cells as well
as intermediate and final toxic metabolites of disturbed
metabolism, what prevents their re-sorption and finally
decreases metabolic and toxic load on excretion or-
gans, first of all — liver and kidneys. One of the most
important properties of enterosorbents, especially
carbon ones, is their ability to bind effectively bacterial
endotoxins (BET) [27]. In the case of ES introduction
into CP chemotherapy, this property of enterosorbents
is of particular importance because of the fact that
a
b
c
Fig. 4. Morphological structure of innate organs in Guerin
carcinoma-bearing rats upon CP+ES treatment (х 200): a — ap-
pearance of hepatocytes with more basophilic cytoplasm and
dense nucleus; b — renal tubules possess normal morphological
structure; c — lymphoid follicle with large marginal zone in spleen
0
2
4
6
8
10
12
14
16
0 5 10 15
Time after the first CP injection, days
Tumor
Tumor+ES
Tumor+CP
Tumor+CP+ES
K
Fig. 5. Dynamic of Guerin carcinoma growth
Experimental Oncology 35, 45–52, 2013 (March) 51
BET synergistically promote CP nephrotoxicity: single
administration of CP or BET to mice doesn’t cause renal
dysfunction however their combined administration
leads to the development of severe renal failure [28].
The obtained results allow conclude that ES at the
regimen of daily use of active enterosorbents just
1 h after CP administration possesses detoxicating
potential sufficient for significant elimination of toxic
effect of the cytostatic at the background of complete
preservation of its antitumor activity. Apart from this,
a drastic alteration of morphological picture of kid-
neys in tumor-bearing animals treated by combined
CP-sorption therapy compared to that in animals
treated with CP alone, allows to suggest that ES could
be capable to affect gene expression in kidney tissues;
such phenomenon has been registered earlier in the
study of effect of carbon eneterosorbent administra-
tion on renal failure development modeled in rats [23].
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Copyright © Experimental Oncology, 2013
|
| id | nasplib_isofts_kiev_ua-123456789-139113 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-11-28T00:00:03Z |
| publishDate | 2013 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Sakhno, L.A. Yurchenko, O.V. Maslenniy, V.N. Bardakhivskaya, K.I. Nikolaeva, V.V. Ivanyuk, A.A. Shevchuk, O.O. Korotich, V.G. Nikolaev, V.G. 2018-06-19T19:14:11Z 2018-06-19T19:14:11Z 2013 Enterosorption as a method to decrease the systemic toxicity of cisplatin / L.A. Sakhno, O.V. Yurchenko, V.N. Maslenniy, K.I. Bardakhivskaya, V.V. Nikolaeva, A.A. Ivanyuk, O.O. Shevchuk, V.G. Korotich, V.G. Nikolaev // Experimental Oncology. — 2013. — Т. 35, № 1. — С. 45-52. — Бібліогр.: 28 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139113 A perspective adsorptive method to minimize systemic toxic effects of chemotherapy is enterosorption (ES). However, the capabilities of this method are far from being completely studied. The question remains opened — should ES be initiated in the first hours on completing cytostatic infusion without the risk of their anticancer activity to be decreased. Aim: to analyze ES influence on anticancer activity and toxic reactions of cisplatin (CP) upon the use of carbon enterosorbent in 1 h after intravenous administration of cytostatic. Methods: CP at the dose of 1 mg/kg body weigh (BW) was administered to Guerin carcinoma-bearing rats each second day for two weeks. Enterosorbents on the basis of highly activated carbon fibers were administered by per os daily 1 h after CP injection. 3 days after the last CP administration the rats were weighted and blood under ether narcosis has been taken for biochemical examination. Tumors and innate organs were isolated, weighted, and fixed in 4% buffered formalin for morphologic examination. Results: In rats administered with CP at the background of ES, BW loss was in 1.6 times lower than in animals after CP session. Relative kidney weight in CP-treated rats was 33.9% higher than in normal ones (p ≤ 0.05). No significant differences were detected between relative kidney weights in the CP + ES-treated and intact animals. Introduction of ES allowed prevent an 30% increase of creatinin content observed in blood plasma after CP treatment (р ≤ 0.05). Urea content was 1.7 times lower in blood plasma of CP + ES-treated rats than after CP treatment. CP caused significant toxic injuries in kidneys, liver, and spleen tissues. Morphologic structure of organs in rats treated with CP at the background of ES was affected at much lower degree. In tumors, large areas of newly formed connective tissue and blood vessels have been fixed after the CP+ES action instead of large necrotic area observed after CP treatment. ES caused insignificant suppression of Guerin carcinoma growth and had additional impact to inhibitory action of CP. Conclusion: Active carbon enterosorbents which are administrated just 1 h after CP administration possesses detoxicating potential sufficient for significant elimination of toxic effect of the cytostatic at the background of complete preservation of its antitumor activity. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Enterosorption as a method to decrease the systemic toxicity of cisplatin Article published earlier |
| spellingShingle | Enterosorption as a method to decrease the systemic toxicity of cisplatin Sakhno, L.A. Yurchenko, O.V. Maslenniy, V.N. Bardakhivskaya, K.I. Nikolaeva, V.V. Ivanyuk, A.A. Shevchuk, O.O. Korotich, V.G. Nikolaev, V.G. Original contributions |
| title | Enterosorption as a method to decrease the systemic toxicity of cisplatin |
| title_full | Enterosorption as a method to decrease the systemic toxicity of cisplatin |
| title_fullStr | Enterosorption as a method to decrease the systemic toxicity of cisplatin |
| title_full_unstemmed | Enterosorption as a method to decrease the systemic toxicity of cisplatin |
| title_short | Enterosorption as a method to decrease the systemic toxicity of cisplatin |
| title_sort | enterosorption as a method to decrease the systemic toxicity of cisplatin |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/139113 |
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