The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin
Aim: To study the influence of doxorubicin at low doses on antitumor action of activated (LAK) and non-activated lymphocytes from lymph nodes toward tumor cells of mice bearing doxorubicin-resistant and doxorubicin-sensitive transplantable MC-rhabdomyosarcoma and B16 melanoma. Materials and Methods:...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2008
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| Назва видання: | Experimental Oncology |
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| Цитувати: | The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin / N.M. Berezhnaya, Yu.D. Vinnichuk, O.B. Belova // Experimental Oncology. — 2008. — Т. 30, № 1. — С. 52–55. — Бібліогр.: 15 назв. — англ. |
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irk-123456789-1392292018-06-20T03:12:13Z The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin Berezhnaya, N.M. Vinnichuk, Yu.D. Belova, O.B. Uncategorized Aim: To study the influence of doxorubicin at low doses on antitumor action of activated (LAK) and non-activated lymphocytes from lymph nodes toward tumor cells of mice bearing doxorubicin-resistant and doxorubicin-sensitive transplantable MC-rhabdomyosarcoma and B16 melanoma. Materials and Methods: The study was carried out on BALB/c mice bearing MC-rhabdomyosarcoma and С57BL/6 mice bearing В16 melanoma. Explants, tumor cells and lymphocytes were cultivated in diffusion chambers, filters were stained with hematoxylin by Karachi, and morphology of preparations was examined. Results: At the day 7 of tumor growth in mice bearing resistant MC-rhabdomyosarcoma, non-activated lymphocytes pretreated with low-dose doxorubicin possess the highest antitumor activity, and in mice bearing doxorubicin-resistant B16 melanoma the highest antitumor activity was detected for lymphocytes after combined cultivation with IL-2 and doxorubicin. At the day 14 of tumor growth, LAK obtained from lymphocytes pretreated with doxorubicin possess the highest cytotoxic activity toward resistant tumor cells both of MC-rhabdomyosarcoma and B16 melanoma. There was no such effect in the case of sensitive tumors. Conclusion: To elevate antitumor activity of LAK toward MC-rhabdomyosarcoma and B16 melanoma cells, low doses of doxorubicin could be used at certain conditions of LAK generation. Цель: изучить влияние малых доз доксорубицина на противоопухолевое действие активированных (ЛАК) и неактивированных лимфоцитов лимфатических узлов по отношению к опухолевым клеткам мышей с резистентными и чувствительными к доксорубицину перевивной МХ-рабдомиосаркомой и меланомой В16. Материалы и методы: исследования проведены на мышах линии BALB/c с МХ-рабдомиосаркомой и С57BL/6 c меланомой В16. Эксплантаты, опухолевые клетки и лимфоциты культивировали в диффузионных камерах и окраской фильтров гематоксилином по Караччи. Исследовали морфологическую картину полученных препаратов с учетом критериев роста опухоли. Результаты: сопоставление результатов противоопухолевой активности активированных и неактивированных лимфоцитов, полученных в различных условиях, показало следующее. На 7-е сутки у мышей з резистентной МХ-рабдомиосаркомой наибольшей противоопухолевой активностью обладали неактивированные лимфоциты, предварительно обработанные малыми дозами докорубицина, а у мышей з резистентной меланомой В16 — лимфоциты после сочетанного культивирования с ИЛ-2 и доксорубицином. На 14-е сутки роста опухоли наибольшей цитотоксической активностью обладали ЛАК, полученные из лимфоцитов, предварительно обработанных доксорубицином, в отношении резистентных опухолевых клеток как перевивной МХ-рабдомиосаркомы, так и меланомы В16. Относительно чувствительных клеток указанных опухолей такой эффект не отмечался. Выводы: для усиления противоопухолевой активности ЛАК по отношению к клеткам МХ-рабдомиосаркомы и меланомы В16, резистентных к доксорубицину, могут быть использованы малые дозы доксорубицина при соблюдении определенных условий получения ЛАК. 2008 Article The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin / N.M. Berezhnaya, Yu.D. Vinnichuk, O.B. Belova // Experimental Oncology. — 2008. — Т. 30, № 1. — С. 52–55. — Бібліогр.: 15 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/139229 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Uncategorized Uncategorized |
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Uncategorized Uncategorized Berezhnaya, N.M. Vinnichuk, Yu.D. Belova, O.B. The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin Experimental Oncology |
| description |
Aim: To study the influence of doxorubicin at low doses on antitumor action of activated (LAK) and non-activated lymphocytes from lymph nodes toward tumor cells of mice bearing doxorubicin-resistant and doxorubicin-sensitive transplantable MC-rhabdomyosarcoma and B16 melanoma. Materials and Methods: The study was carried out on BALB/c mice bearing MC-rhabdomyosarcoma and С57BL/6 mice bearing В16 melanoma. Explants, tumor cells and lymphocytes were cultivated in diffusion chambers, filters were stained with hematoxylin by Karachi, and morphology of preparations was examined. Results: At the day 7 of tumor growth in mice bearing resistant MC-rhabdomyosarcoma, non-activated lymphocytes pretreated with low-dose doxorubicin possess the highest antitumor activity, and in mice bearing doxorubicin-resistant B16 melanoma the highest antitumor activity was detected for lymphocytes after combined cultivation with IL-2 and doxorubicin. At the day 14 of tumor growth, LAK obtained from lymphocytes pretreated with doxorubicin possess the highest cytotoxic activity toward resistant tumor cells both of MC-rhabdomyosarcoma and B16 melanoma. There was no such effect in the case of sensitive tumors. Conclusion: To elevate antitumor activity of LAK toward MC-rhabdomyosarcoma and B16 melanoma cells, low doses of doxorubicin could be used at certain conditions of LAK generation. |
| format |
Article |
| author |
Berezhnaya, N.M. Vinnichuk, Yu.D. Belova, O.B. |
| author_facet |
Berezhnaya, N.M. Vinnichuk, Yu.D. Belova, O.B. |
| author_sort |
Berezhnaya, N.M. |
| title |
The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin |
| title_short |
The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin |
| title_full |
The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin |
| title_fullStr |
The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin |
| title_full_unstemmed |
The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin |
| title_sort |
use of doxorubicine at low doses for elevation of lak-activity toward explants and cells of mc-rhabdomyosarcoma and в16 melanoma resistant to doxorubicin |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2008 |
| topic_facet |
Uncategorized |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/139229 |
| citation_txt |
The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and В16 melanoma resistant to doxorubicin / N.M. Berezhnaya, Yu.D. Vinnichuk, O.B. Belova // Experimental Oncology. — 2008. — Т. 30, № 1. — С. 52–55. — Бібліогр.: 15 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-10T07:50:26Z |
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2025-07-10T07:50:26Z |
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| fulltext |
52 Experimental Oncology 30, 52–55, 2008 (March)
It is known that tumors resistant to anticancer prepa
rations in the majority of cases demonstrate marked
aggressiveness and ability to quick progression.
Combination of chemoresistance with the resistance
to radio and phototherapy additionally complicates
the treatment of the patients with chemoresistant tu
mors [1]. The problem of therapy of the patients with
chemoresistant tumors requires not only improvement
of the therapy with already existing preparations and
the development of new ones, but also the search for
new approaches for treatment of such patients.
In our earlier studies we have shown that the cells
and explants of human chemoresistant tumors (soft
tissue tumors of locomotor system, and epithelial
tumors of female reproductive system) and animal
tumors (В16 melanoma and transplantable MC
rhabdomyosarcoma) demonstrate elevated sensi
tivity to the action of LAK [2, 3]. This fact has been
proved not only in the study in vitro, but also upon
immunotherapy of mice bearing doxorubicinresistant
MCrhabdomyosarcoma [4]. To study the sensitivity of
explants of human tumors, we have used the method
developed by us for determination of individual sen
sitivity to preparations widely used for chemotherapy
(doxorubicin, methotrexate, vincristine, carboplatin,
cyclophosphan). It is necessary to note that the phe
nomenon of elevated sensitivity of resistant tumors
to the action of LAK was observed even if there was
resistance only to a single preparation [3].
So, the question arises — is it possible to elevate an
titumor action of LAK against chemoresistant tumors?
As one approach, we have used doxorubicin (Dox) at
the low doses — according to the data of literature, this
drug and a number of other chemopreparations pos
sess immunomodulating effect at the low doses.
For example, low doses Dox may promote functions
of the cells of immune system, in particular peritoneal
exudate (macrophages, neutrophils, lymphocytes)
and elevate production of INFγ, TNFα [5, 6]. The use
of low (subtoxic) doses of chemopreparations returns
to lymphocytes the ability for cytotoxic action toward
chemoresistant renal and prostate tumors that is reali
zed via perforindependent and perforinindependent
mechanisms [7]. The authors concluded that the use
of the low doses of chemopreparations results in “sen
sibilization” of chemoresistant tumors.
Dox at the low doses may promote effect of TNFα,
as it was shown in the experiments with EL4resistant
murine lymphoma cells. Antitumor activity of cytotoxic
splenocytes and thymocytes increased, and such in
crease correlated with elevated survival of mice. The
effect was observed also for spleen macrophages and
LAK [8]. Doxorubicin possesses ummunomodulatory
action, and if it is used as a component of copolymer
Doximmunoglobulin, activity of LAK and natural killer
cells was higher [6].
There are other preparations able to promote tumor
cell lysis; for example, mitomycin and cysplatin may
elevate the sensitivity of colon cancer cells of SW480
line to apoptotic signals [9]. The treatment of human
ovarian cancer cells of SVO3 line with paclitaxel ele
vated their sensitivity to LAKmediated lysis [10].
Unfortunately, the number of studies aimed on
evaluation of antitumor activity of LAK against resistant
tumor cells using low doses of Dox or other antican
cer preparations is limited. That’s why the present
research was directed on the development of optimal
The use of doxorubicine aT low doses for elevaTion
of lak-acTiviTy Toward explanTs and cells
of mc-rhabdomyosarcoma and В16 melanoma resisTanT
To doxorubicin
N.M. Berezhnaya*, Yu.D. Vinnichuk, O.B. Belova
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
Aim: To study the influence of doxorubicin at low doses on antitumor action of activated (LAK) and non-activated lymphocytes from lymph
nodes toward tumor cells of mice bearing doxorubicin-resistant and doxorubicin-sensitive transplantable MC-rhabdomyosarcoma and
B16 melanoma. Materials and Methods: The study was carried out on BALB/c mice bearing MC-rhabdomyosarcoma and С57BL/6
mice bearing В16 melanoma. Explants, tumor cells and lymphocytes were cultivated in diffusion chambers, filters were stained with
hematoxylin by Karachi, and morphology of preparations was examined. Results: At the day 7 of tumor growth in mice bearing resistant
MC-rhabdomyosarcoma, non-activated lymphocytes pretreated with low-dose doxorubicin possess the highest antitumor activity,
and in mice bearing doxorubicin-resistant B16 melanoma the highest antitumor activity was detected for lymphocytes after combined
cultivation with IL-2 and doxorubicin. At the day 14 of tumor growth, LAK obtained from lymphocytes pretreated with doxorubicin
possess the highest cytotoxic activity toward resistant tumor cells both of MC-rhabdomyosarcoma and B16 melanoma. There was
no such effect in the case of sensitive tumors. Conclusion: To elevate antitumor activity of LAK toward MC-rhabdomyosarcoma and
B16 melanoma cells, low doses of doxorubicin could be used at certain conditions of LAK generation.
Key Words: transplantable MC-rhabdomyocarcoma, melanoma, resistance, doxorubicin, LAK.
Received: October 15, 2007.
*Correspondence: E-mail: berezh@onconet.kiev.ua
Abbreviations used: Dox – doxorubicin; LAK — lymphokine-acti-
vated killer cells.
Exp Oncol 2008
30, 1, 52–55
Experimental Oncology 30, 52–55, 2008 (March) 5330, 52–55, 2008 (March) 53March) 53) 53 53
conditions for elevation of antitumor activity of LAK
against Doxresistant tumors.
maTerials and meThods
In the study, BALB/c and C57BL/6 mice weighting
15–20 g bred in the vivarium of R.E. Kavetsky Institute
of Experimental Pathology, Oncology and Radiobiolo
gy, NAS of Ukraine (Kyiv, Ukraine) were used. As ex
perimental tumor models, we have used the strains
generated by us: 1) В16 melanoma and transplantable
MCrhabdomyosarcoma cells resistant to Dox; 2) В16
melanoma and transplantable MCrhabdomyosar
coma cells sensitive to Dox.
The studies were performed on tumor explants
and isolated tumor cells and lymphocytes from lymph
nodes of experimental animals.
Lymphokineactivated cells (LAK) were obtained
by incubation of lymphocytes of lymph nodes of tumor
bearing mice with recombinant IL2 (3 x 106 cells with
1000 МU RIL2) for 2 h at 37 °С.
Lymphocytes and LAK were treated with 0.4 µg/ml
doxorubicin (Ebeve, Austria) for 24 h in complete
RPMI1640 medium at 37 °С. The optimal dose and
conditions of cultivation were estimated prior to
experiments (calibration of preparation dose at the
base of therapeutic one accounting animals weight,
has been done).
The following systems of cultivation in diffusion
chambers were used: 1) cultivation of lymphocytes,
Doxpretreated, with tumor cells or explants; 2) cul
tivation of LAK, Doxpretreated, with tumor cells or
explants; 3) cultivation of tumor cells or lymphocytes
after combined treatment with Dox and IL2. Controls
were as follow: 1) tumor growth at standard condi
tions; 2) the growth of tumor cells with nonactivated
lymphocytes; 3) the growth of tumor cells with LAK.
Evaluation of antitumor action of lymphocytes was
performed at the base of tumor growth morphology
[05]. All experiments were done with the use of the cells
and explants of both Doxsensitive and Doxresistant
MCrhabdomyosarcoma and B16 melanoma.
resulTs and discussion
The study of anticancer activity of LAK received
from lymphocytes from lymph nodes of mice was car
ried out in the dynamics of tumor growth (at the days 7
and 14 after tumor transplantation). At the day 7, tumor
explants were studied because it was impossible to
receive required quantity of tumor cells (at this period
tumors were too small (0.06–0.09 g)), and at the day 14
isolated tumor cells and explants were examined.
At the day 7 after tumor transplantation, the com
parative study of antitumor action of nonactivated
lymphocytes and LAK from animals bearing transplant
able MCrhabdomyosarcoma resistant and sensitive
to Dox upon the influence of low doses of the drug has
shown the following: upon cultivation of lymphocytes
from mice bearing resistant MCrhabdomyosarcoma
it has been shown that pretreatment of nonactivated
lymphocytes with Dox elevated their cytotoxicity to
the level of LAK; pretreatment of LAK with Dox did not
alter their antitumor action. Lymphocytes cultivated
with IL2 and Dox possess the same antitumor activ
ity. In the case of sensitive tumor, pretreatment of
lymphocytes with Dox did not alter antitumor action
of nonactivated lymphocytes, but elevated antitumor
activity of LAK (Fig. 1).
0
1
2
3
4
Resistant MC-rhabdomyosarcoma
Sensitive MC-rhabdomyosarcoma
Control Lympho-
cytes
Lympho-
cytes + DOX
LAK LAK + DOX Lymphocytes
+ IL-2 + DOX
fig. 1. Antitumor action of lymphocytes of mice bearing trans
plantable MCrhabdomyosarcoma resistant and sensitive to
doxorubicine at day 7 after tumor transplantation. 1 — migration
of single cells, initial stages of formation of the monolayer; 2 — in
tense formation of monolayer; 3 — single conglomerates
In analogous way, the study was performed for
lymphocytes and tumor cells of mice bearing mela
noma В16 sensitive and resistant to Dox. In the case of
resistant tumor explants, the highest antitumor activity
was observed for lymphocytes cultivated with IL2 and
Dox. However, pretreatment with Dox did not alter cy
totoxic activity of lymphocytes and LAK (which activity
was higher than that of lymphocytes). In the case of
sensitive tumor explants, pretreatment of lymphocytes
with Dox led to elevation of their cytotoxic activity to
the level of that of LAK; the influence of pretreatment
of LAK with Dox or its combination with IL2 was not
observed (Fig. 2).
0
1
2
3
4 Resistant melanoma Â16
Sensitive melanoma Â16
Control Lympho-
cytes
Lympho-
cytes + DOX
LAK LAK + DOX Lymphocytes
+ IL-2 + DOX
fig. 2. Antitumor action of lymphocytes of mice bearing
melanoma B16 resistant and sensitive to doxorubicine at day 7
after tumor transplantation. 1 — migration of single cells, initial
stages of formation of the monolayer; 2 — intense formation of
monolayer; 3 — single conglomerates; 4 — intense formation
of conglomerates
Comparison of the results of antitumor activity of
activated and nonactivated lymphocytes received at
different conditions against the explants of the resis
tant В16 melanoma and transplantable MCrhabdo
myosarcoma revealed some differences; in particular,
the pretreatment of nonactivated lymphocytes with
Dox at low doses elevated their antitumor activity upon
cultivation with MCrhabdomyosarcoma explants, but
54 Experimental Oncology 30, 52–55, 2008 (March)
not in the case of melanoma cells. The highest antitu
mor activity against melanoma cells was observed for
lymphocytes incubated with IL2 and Dox. It is neces
sary to note that in the case of MCrhabdomyosarcoma
cells, antitumor activity of lymphocytes elevated after
using all variants of pretreatment (see Fig. 1, 2).
At the day 14 after tumor transplantation, in the
case of resistant MCrhabdomyosarcoma the highest
antitumor action was registered for LAK obtained from
lymphocytes pretreated with Dox. The pretreatment
with Dox did not influence the activity of nonactivated
lymphocytes; cultivation of lymphocytes with IL2 and
Dox also did not elevate their antitumor action (Fig. 3).
For resistant melanoma B16 cells, the highest activity
was registered for LAK obtained from lymphocytes
pretreated with Dox; Doxpretreatment of nonac
tivated lymphocytes also elevated their antitumor
potency. Similarly to MCrhabdomyosarcoma model,
combined treatment did not influence antitumor action
of lymphocytes (Fig. 4).
0
1
2
3
4
Control Lympho-
cytes
Lympho-
cytes + DOX
LAK LAK + DOX Lymphocytes
+ IL-2 + DOX
fig. 3. Antitumor action of lymphocytes of mice bearing trans
plantable MCrhabdomyosarcoma resistant and sensitive to
doxorubicine at day 14 after tumor transplantation. 1 — migration
of single cells, initial stages of formation of the monolayer; 2 — in
tense formation of monolayer; 3 — single conglomerates
0
1
2
3
4
Control Lympho-
cytes
Lympho-
cytes + DOX
LAK LAK + DOX Lymphocytes
+ IL-2 + DOX
fig. 4. Antitumor action of lymphocytes of mice bearing melano
ma В16 resistant to doxorubicine at day 14 after tumor transplan
tation. 1 — migration of single cells, initial stages of formation of
the monolayer; 2 — intense formation of monolayer; 3 — single
conglomerates; 4 — intense formation of conglomerates
The common pattern of lymphocytes from mice
bearing sensitive MCrhabdomyosarcoma and В16
melanoma was the absence of influence of Doxpre
treatment on their antitumor activity.
As it was mentioned above, the task of present re
search was the development of approach for elevation
of antitumor activity of LAK against chemoresistant
tumors (MCrhabdomyosarcoma, В16 melanoma)
using low doses of Dox. The use of different systems
for cultivation of lymphocytes from mice bearing Dox
sensitive and Doxresistant tumors allowed to show
that, firstly, the conditions for elevation of activity of
LAK against Doxresistant tumors differ from these
for Doxsensitive mice; secondly, the influence of low
doses of Dox on antitumor activity of lymphocytes from
mice with Doxresistant MCrhabdomyosarcoma and
В16 melanoma is also different, especially at early
stages of tumor growth.
Such effect of Dox one could explain by its ability
for imunomodulating action. It is known that the total
population of LAK is heterogeneous and is presented
by different subpopulations of killer cells [11]. Accord
ing to the data of literature, Dox may elevate the activity
of different cells of immune system. In particular, the
data showing that upon the development of resistance
to adriamycin, increased expression of I class antigens
of histocompatibility complex (А, B, C) in ovarian
cancer cells promoting their lysis, point on the pos
sibility of activation of cytotoxic Tlymphocytes [12].
The influence of adriamycin is not limited by cytotoxic
Tlymphocytes, but involves also natural killer cells
and LAK; this fact has been shown upon the study of
bladder cancer cells, lymphocytes of peripheral blood
and lymphocytes infiltrating tumor [13]. The authors
consider that the treatment of tumor cells with low
doses of adrsamycin induces their elevated sensitivity
to the action of different killer cells. The similar point
of view has been documented in another study where
elevated expression of ICAM1 in ovarian cancer cells
resistant to packlitaxel considered as a main cause
of elevated sensitivity of the cells to LAK action, has
been reported [10]. The data on positive influence of
low dose Dox on Doxresistant tumor cells are in ac
cordance with our earlier results for in vivo and in vitro
studies that showed that simultaneous introduction of
Dox and LAK to mice bearing Doxresistant MCrhab
domyosarcoma promoted the effect of LAK [2].
In summary, one may conclude that the effect of
low dose Dox is a result of both elevated activity of
different killer cells and increased sensitivity of the
tumor to their action. The presented data are sup
porting the reported earlier results and show that low
dose Dox may be used for treatment of tumor cells and
for generation of LAK possessing higher activity, and
these effects are complementary. That’s why one may
consider that the low doses of anticancer drugs may be
used in regular chemotherapy, and immunomodulating
effect of Dox will not be suppressed [14].
The results of the present study have shown that for
elevation of antitumor activity of LAK toward Doxresis
tant MCrhabdomyosarcoma and В16 melanoma cells,
low dose Dox could be used upon special conditions
of LAK generation. These data make reasonable the
further study of the processes responsible for elevated
sensitivity of resistant tumor cells to cytotoxic action
of lymphocytes and of optimizing effect of low dose
Dox; the research of expression of surface molecules
Experimental Oncology 30, 52–55, 2008 (March) 5530, 52–55, 2008 (March) 55March) 55) 55 55
on lymphocytes and resistant tumor cells will be es
pecially important.
references
1. Koppold B, Sauer G, Buening H, et al. Chemotherapeu-
tic agents enhance AAV2-mediated gene transfer into breast
cancer cells promoting CD40 ligand-based immunotherapy.
J Cancer Res Clin Oncol 2006; 132: 787–94.
2. Berezhnaya NM, Kovalchuk EV, Spivak SI, et al. An-
titumor action of lymphocytes in the dynamics of formation
of the resistanse to doxorubicine in mice bearing transplant-
able MC-rhabdomyosarcoma. Exp Oncol 2002; 24: 292–5
(In Russian).
3. Berezhnaya NM, Vinnichuk YD, Konovalenko VF, et al.
The sensitivity of chemioresistant human tumor explants to
lysis by activated and nonactivated autological lymphocytes:
a pilot study. Exp Oncol 2005; 27: 303–7.
4. Berezhnaya NM, Kovalchuk EV, Vinnichuk YD, et al.
Experimental immunotherapy of mice with transplated
MC-rhabdomiocarcoma resistant to doxorybicin. Exp Oncol
2004; 26: 63–7.
5. Eralp Y, Wang X, Wang JP. Doxorubicin and paclitaxel
enhance the antitumor efficacy of vaccines directed against
HER 2/neu in a murine mammary carcinoma model. Breast
Cancer Res. 2004; 6: 275–83.
6. Rihova B, Strohalm J, Prausova J. Cytostatic and immu-
nomobilizing activities of polymer-bound drugs: experimental
and first clinical data. J. Control Release 2003; 91: 1–16.
7. Frost P, Caliliw R, Belldegrun A, et al. Immunosensitiza-
tion of resistant human tumor cells to cytotoxicity by tumor
infiltrating lymphocytes. Int J Oncol 2003; 22: 431–7.
9. Ehrke MJ, Verstovsek S, Maccubbin DL, et al. Protective
specific immunity induced by doxorubicin plus TNF-alpha
combination treatment of EL4 lymphoma-bearing C56BL/6
mice. Int J Cancer 2000; 87: 101–9.
10. Zhu Q, Liu JY, Yang CM, et al. Influence of antitumor
drugs on the expression of Fas system in SW480 colon cancer
cells. Eur J Gastroenterol Hepatol 2006; 18: 1071–7.
11. Law KS, Chen HC, Liao SK. Non-cytotoxic and
sublethal paclitaxel treatment potentiated the sensitivity of
cultured ovarian tumor SKOV-3 cells to lysis by lymphokine-
activated killer cells. Anticancer Res 2007; 27: 841–50.
12. Bereznaya NM, Koval’chuk EV. LAK-phenomenon
(cell phenotype, mechanism of action and conditions for its
realization). Immunologiya 1995; 2: 12–6 (In Russian).
13. Fisk B, Ioannides CG. Increased sensitivity of adriami-
cin-selected tumor lines to CTL-mediated lysis results in
enchanced drug sensitivity. Cancer Res 1998; 58: 4790–3.
14. MizutaniY, Yoshida O, Miki T. Adriamycin-mediated
potentiation of cytotoxicity against freshly isolated bladder
cancer cells by autologous non-activated peripheral blood
lymphocytes and tumor infiltrating lymphocytes. J Urol 1999;
162: 2171–5.
15. Zagozdzon R, Golab J. Immunomodulation by anti-
cancer chemotherapy: more is not always better (review). Int
J Oncol 2001; 18: 417–24.
ИспользоВанИе малых доз доксорубИцИна
для усИленИя актИВностИ лак В отношенИИ
эксплантатоВ И опухолеВых клеток
мх-рабдомИосаркомы И меланомы В16, резИстентных
к доксорубИцИну
Цель: изучить влияние малых доз доксорубицина на противоопухолевое действие активированных (ЛАК) и неактивированных
лимфоцитов лимфатических узлов по отношению к опухолевым клеткам мышей с резистентными и чувствительными к
доксорубицину перевивной МХ-рабдомиосаркомой и меланомой В16. Материалы и методы: исследования проведены на
мышах линии BALB/c с МХ-рабдомиосаркомой и С57BL/6 c меланомой В16. Эксплантаты, опухолевые клетки и лимфоциты
культивировали в диффузионных камерах и окраской фильтров гематоксилином по Караччи. Исследовали морфологическую
картину полученных препаратов с учетом критериев роста опухоли. Результаты: сопоставление результатов противоопухолевой
активности активированных и неактивированных лимфоцитов, полученных в различных условиях, показало следующее.
На 7-е сутки у мышей з резистентной МХ-рабдомиосаркомой наибольшей противоопухолевой активностью обладали
неактивированные лимфоциты, предварительно обработанные малыми дозами докорубицина, а у мышей з резистентной
меланомой В16 — лимфоциты после сочетанного культивирования с ИЛ-2 и доксорубицином. На 14-е сутки роста опухоли
наибольшей цитотоксической активностью обладали ЛАК, полученные из лимфоцитов, предварительно обработанных
доксорубицином, в отношении резистентных опухолевых клеток как перевивной МХ-рабдомиосаркомы, так и меланомы В16.
Относительно чувствительных клеток указанных опухолей такой эффект не отмечался. Выводы: для усиления противоопухолевой
активности ЛАК по отношению к клеткам МХ-рабдомиосаркомы и меланомы В16, резистентных к доксорубицину, могут быть
использованы малые дозы доксорубицина при соблюдении определенных условий получения ЛАК.
Ключевые слова: перевивная МХ-рабдомиосаркома, меланома В16, резистентность, доксорубицин, ЛАК.
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