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Reproductive toxicity of cytoReproductive toxicity of cyto--static static drugs and pharmacological ways to drugs and pharmacological ways to
reduce itreduce it
by Tatyana Borovskaya
Laboratory of Pharmacology of Reproductive SystemThe Goldberg Research Institute of Pharmacology, Tomsk, RUSSIA
Intensity of reproductive dysfunction in women with cancer under different treatment regimens
amenorrhea COPPHemoblastosis
amenorrhea in 88%
amenorrhea in 55%
СМF
FAC
Breast Cancer
Status of reproductive
functionSchemeDisease
Does not result in sterilizationPOMB/ACEOvarian cancer (after conserving surgery)
amenorrhea
amenorrhea in the majority of
amenorrhea women
Violations in ovarian cycle are minimal
COPP
EEACOPP
CHOP
ABVD
Hemoblastosis
*Berthon L. (1987). Traitements anticancereux et fertilite. J. France Medicine, 94:247-8.
*Mormor D. (1993). Fertile après traitements cytostatiques. Contracept.-fertil.-sex., 21(10):739-43.
*Evain P.L. Bazonzelly M., Dusol F., Demaille M. (1986).Chemiotherapia anticancereuse at fertilite cher la femime. Rev. Fr. gynecolog at obsted., 3:451-4. gynecolog at obsted., 3:451-4.
*Howell S.G., Shalet S.M. (2001). Testicular function following chemoterapy. Human Reprod. Update, 7 (4):3369-3.
*Taksey Y, dissada N.K., Chayndhary U.B. (2003). Fertility after chemotherapy for testicular cancer. Arch. Androl., 49(5):389-95.
Group and name of the drug,Group and name of the drug,chemical structurechemical structure
Main mechanism of antiMain mechanism of anti--tumor actiontumor action
PLATINUM COMPLEXES
Сisplatin, Сisplatin, Lachema ACLachema AC, , AustriaAustria
Form a crossForm a cross--link between DNA moleculeslink between DNA molecules
Carboplatin, Carboplatin, EBEWE PharmaEBEWE Pharma, , AustriaAustria
ANTHRACYCLINE ANTIBIOTICS
Doxorubicin, Doxorubicin, EBEWE PharmaEBEWE Pharma, , AustriaAustriaDoxorubicin, Doxorubicin, EBEWE PharmaEBEWE Pharma, , AustriaAustriaIntercalation between the base pairs of Intercalation between the base pairs of DNADNA
Epirubicin, Epirubicin, Karlo ArbaKarlo Arba, Italy, Italy
INHIBITORS TOPOIZOMERAZNOY ACTIVITY
Еtoposide, Еtoposide, Teva Pharmaceutical IndustriesTeva Pharmaceutical Industries, , IsraelIsrael IInhibition of topoisomerase nhibition of topoisomerase IIII
TAXOIDS
Paclitaxel, Paclitaxel, Dr ReddisDr Reddis, I, Indiandia Stimulation of assembling of anomalous Stimulation of assembling of anomalous
microtubules microtubules
The object of study is Wistar rats
The drugs were administered intravenously in asingle MTD, because in clinics high-dosetherapy is used
Methods of study
morphological
Research terms
The assessment of effects was performed 3 and 6 months after administration of cyto-static drugs
•• morphological (using quantitative indicators characterizing extent of the damage)• • functional(fertility index, the index pregnancy, fetal death)
gonads testes
Early antiproliferative effects of cytotoxic drugs on gonads
On testicular tissue:
БA
"DNA-comets" of mouse testis
On ovarian tissue::
Death of follicular epithelium cells
B
Tubules with the 12th stage of meiosis, %
Number of normal spermatogonia, % of control
0 30 60 90 120 150 1800
300
600
900
1200
Primordial follicles
А – cells with DNA-damages
B – Apotopic"DNA-comets"
Control Epirubicin Etoposide Doxorubicin Cisplatin Paclitaxel
Content of structural-functional elements of rats ovaries, 6 months after a single injection of anticancer drugs in the MTD (% of control)
Ep – Epirubicin; Cs – Cisplatin; Cr – Carboplatin; Et – Etoposide; P – Paclitaxel
Ep Cs Cr Et P Ep Cs Cr Et P Ep Cs Cr Et P
Primordial follicles Double or multiple follicles Graafian folliclesTotal number of generative
elements
Intensity of long-term-late effects of cyto-static drugs on structural and functional elements of the rat ovary is decreased
in the following order:
Epirubicin
Etoposide
Paclitaxel
Cisplatin
Carboplatin
Efficiency of mating in female-rats in the long-term period after administration of cytotoxic drugs of different groups
60
80
100
Ep – Epirubicin; Cs – Cisplatin; Cr – Carboplatin; Et – Etoposide; P – Paclitaxel
0
20
40
Percentage of control
Ep Cs Cr Et P
60
80
100
Embryonic mortality in female rats while the crossbreeding long-term period after administration of cito-static drugs of different groups
(% of control)
*
* ** *
Ep – Epirubicin; Cs – Cisplatin; Cr – Carboplatin; Et – Etoposide; P – Paclitaxel
0
20
40
Preimplantation mortality Postimplantation mortality
Ep Cs Cr Et PEp Cs Cr Et P
* *
Toxic effect of drugs on embryonic mortality is decreased in the following order:
Taxanes
Inhibitors of topo-Inhibitors of topo-isomerase activity
Anthracycline antibiotics
Platinoids
Morphological status of the testes of rats at 3 months after administration
of Paclitaxel and Epirubicin
Intact rat testis, age 5.5 months, x160.
Staining with hematoxylin and eosin.
Testis rats 3 months after administration of
Paclitaxel and / or Epirubicin, x160.
Thinning seminiferous epithelium. Staining
with hematoxylin and eosin.
60
80
100
120
*
*
Sperm count, and efficiency of mating male rats at 3 months after administration of cyto-static drugs of different groups
0
20
40
60
Total sperm count, million Efficiency of mating, % of
control
Ep Cr Cs Et P Ep Cr Cs Et P
*
* *
Ep – Epirubicin; Cs – Cisplatin; Cr – Carboplatin; Et – Etoposide; P – Paclitaxel
State of reproductive system of male rats long-term after administration of cyto-static drugs of different groups
DrugDrug SSexual instinctexual instinct FertilityFertility
Level ofLevel of (DLM)(DLM)(characterizes the (characterizes the probability to save probability to save
pregnancy)pregnancy)
Platidiam Not disturbed Not disturbed Not increased
Сarboplatin Not disturbed Not disturbed Not increased
Pharmorubicin Not disturbed Infertility, 100 % Not increased
Doxorubicin Not disturbed Not disturbed Not increased
Etoposide Not disturbed Not disturbed Increased
Paclitaxel Not disturbed Infertility, 100 % Increased
Toxicity decreases in the following order:
Pharmorubicin Paclitaxel Etoposide
In platinum drugs toxicity was not found
� Testis tissue biopsy � Cryopreservation
of sperm
Cryopreservation of
� Cryopreservation
of oocytes
Possible ways to reduce the long-term consequences of the effect of cyto-static drugs on reproductive system by assisting
reproductive technologies
IVF
ISI
� Cryopreservation of ovarian tissue � Cryopreservation of
embryos
� Differentiation of bone
marrow stem cells into male
germ cells
Negative aspects of assisted reproductive technologies:
1. High cost
2. Inability to perform due to the need to start chemotherapy
3. high sensitivity of oocytes to freezing
Comments:IVF - in vitro fertilization
ISI - Intracytoplasmic Sperm
Injection
чССК - human spermatogonial
stem cell
�Stimulator of spermatogenesis
�Gonadal-hormone products
�Hypothalamic regulators of pituitary function
[Carmely A., 2009].
� Immunomodulators
Drugslimiting apoptosis in oocytes (sfignozin monophosphate)
The effectiveness of drug therapy as the way to reduce the effects of cyto-static gonadotoxicity
spermatogenesis (testosterone)
of pituitary function
[Kolomietz О.L. et al., 2001;Borovskaya Т.G. et al., 2003]
Эффективность низкая
[Delis J. et al., 1987]
[Bоcker L. et al., 1990; Borovskaya Т.G. et al., 2007]
Low
efficiency
Widely used in
clinic, highly
effective
[Tilly J.L. et al., 2004]
monophosphate)
� Means of regenerative medicine
[Borovskya Т.G., Dygai А.М., Zhdanov V.V., 2008]
�Antioxidants
Negative aspects:
1.High cost
2.Inability to perform due to the need
to start chemotherapy
Number of structural and functional elements of rats ovaries, 6 months after combined administration
of Etoposide and Buserelin
% of control (etoposide)
Primordial follicles
Double andmultiple follicles
Atretic follicle Yellow body
Graafian follicles
Recent years, the new information about the properties of
pluripotent progenitor cells of the body was obtained. The
possibility of mobilizing the internal mechanisms of "deep reserve"
– bone marrow stem cells and their following homing into the
damaged tissue and activation of regional stem cells by various
cytokines is shown.
А.М. А.М. DygaiDygai, , VV..VV. . ZhdanovZhdanov et al.et al.
2006, 2010, 20112006, 2010, 2011
Reparative regeneration of testicular tissue after administration of Paclitaxel
Restoring of spermatogonia goes
under upgrading of spermatogenic
layer
mature seed tubule
immature seed tubule
stem spermatogonia
cell microenvironment - Sertoli cells
Rete
testis
4,5
5
5,5
6
6,5
2 months 3 months0
20
40
60
80
100
Amount of spermatogonia
(% of background)Degree of maturity of spermatogenic
layer (a.u.)
Status of spermatogenesis in rats late after combined administration of paclitaxel with G-CSF and pegylated G-CSF
2 months 3 months 2 months 3 months
0
50
100
150
200
250
2 months 3 months
Total amount of germ cells (% of background)
background
Paclitaxel (control)
Paclitaxel + G-CSF
Paclitaxel + pegylated G-CSF
– differences are significant compared to the background – differences are significant compared to the control
200
250
300
350
400
450
methyimetasulfonate
methyimetasulfonate+antioxidant
Effect of antioxidant from the group of sterically hindered phenols to the level of DNA comets in the testes of mice treated with
methyl-meta-sulphonate or paclitaxel
0
50
100
150
200
% of control
Paclitaxel
Paclitaxel+antioxidant
– differences are significant compared to the background
– differences are significant compared to corresponding control