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Reproductive toxicity of cyto Reproductive toxicity of cyto-static static drugs and pharmacological ways to drugs and pharmacological ways to reduce it reduce it by Tatyana Borovskaya Laboratory of Pharmacology of Reproductive System The Goldberg Research Institute of Pharmacology, Tomsk, RUSSIA

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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

Thank you for

attention!