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
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