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  • 1
    Online Resource
    Online Resource
    Doxorubicin-induced ovarian toxicity
    Springer Science and Business Media LLC ; 2010
    In:  Reproductive Biology and Endocrinology Vol. 8, No. 1 ( 2010-12)
    Details
    In: Reproductive Biology and Endocrinology, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2010-12)
    Abstract: Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries. Methods Female mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin. Results A single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment. Conclusions Our results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary.
    Type of Medium: Online Resource
    ISSN: 1477-7827
    URL: Article
    DOI: 10.1186/1477-7827-8-20
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2119215-7
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Doxorubicin-induced vascular toxicity: Targeting potential pathways to reduce procoagulant activity.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. e13080-e13080
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e13080-e13080
    Abstract: e13080 Background: In a former study in mice using the gonads as an end-organ prototype, we have characterized by real-time intravital imaging an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets’ function and to use potentially protectants to reduce DXR acute effect on the blood flow. Methods: 100 µg/mouse 24 hours and 1 hour prior to DXR treatment (8 mg/kg), or with eptifibatide (integrilin,75µg/mouse) 90min prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound. Platelet adhesion to confluent endothelial cells (EC) was evaluated following exposure of EC to DXR (100 µM) for 4h followed by exposure to whole blood under defined shear rates. Fixed platelets were immunostained by anti- CD41a antibody. DXR effect on platelet adhesion was determined by pre-incubation of platelet rich plasma for 15min with increasing concentrations of DXR and induction of aggregation by ADP. For in vivo study, mice were injected with either LMWH (Enoxaparin; Clexane). Results: There was a significant 3.6-fold increase in platelet adhesion to DXR-exposed EC (p 〈 0.002) reflecting the toxic effect of DXR on EC. Yet, significant DXR- dose dependent decrease in platelet aggregation was observed reaching up to 40% inhibition at 100 µM (p 〈 0.001). Testicular arterial blood flow was preserved as a result of pre-treatment with LMWH or eptifibatide prior to DXR (P 〈 0.01). Conclusions: DXR-induced acute vascular toxicity may trigger the coagulation pathway while enhancing platelet adhesion yet inhibiting massive aggregation, which result in compromised blood flow due to microthrombi formation. Anti-platelet/anti-coagulant agents appear to be effective in reducing the detrimental effect of DXR on the vasculature.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.e13080
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Effect of dexrazoxane on doxorubicin-induced testicular toxicity.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 2556-2556
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 2556-2556
    Abstract: 2556 Background: Seminal advances in anti-cancer therapy result in growing numbers of young male cancer survivors for whom treatment-induced infertility represents a major late-term concern. Doxorubicin (DXR) has been previously shown to exert toxic effect on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we aimed to study its potential effect to reduce DXR-induced testicular toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg DXR or 100mg/kg DEX or the combination of both and scarified at one month post treatment. Saline-injected mice served as controls. Testes were excised, weighed and further processed. For oxidative stress determination glutathione assay was performed on testes' lysates and P38 protein levels were determined by western blot analysis. Bax levels were used to assess apoptosis. Immunohistochemistry and confocal microscopy were used to study the effect of DXR, DEX and their combination, on the testis histology as well as on the spermatogonial reserve. Results: One month after DEX and DXR treatment, a striking decline in testicular weight was observed (decrease by 60% compared with control values; decrease of 54% in DXR-only treated mice; p 〈 0.05). DEX prevented DXR-induced oxidative stress. However, DEX enhanced DXR-induced apoptosis within the testes and furthermore, the combination depleted the spermatogonial reserve one month after treatment. Conclusions: DEX activity in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate DXR-induced testicular toxicity.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.2556
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Anti-Müllerian Hormone Is a Marker for Chemotherapy-Induced Testicular Toxicity
    The Endocrine Society ; 2015
    In:  Endocrinology Vol. 156, No. 10 ( 2015-10-01), p. 3818-3827
    Details
    In: Endocrinology, The Endocrine Society, Vol. 156, No. 10 ( 2015-10-01), p. 3818-3827
    Abstract: Due to increased numbers of young cancer patients and improved survival, the impact of anticancer treatments on fertility has become a major health concern. Despite mounting research on ovarian toxicity, there is paucity of data regarding reliable biomarkers of testicular toxicity. Our aim was to evaluate anti-Müllerian hormone (AMH) as a marker for chemotherapy-induced testicular toxicity. Serum AMH and a panel of gonadal hormones were measured in male cancer patients at baseline and after chemotherapy. In the preclinical setting, mice were injected with diverse chemotherapies and were killed 1 week or 1, 3, or 6 months later. We evaluated spermatogenesis by AMH as well as qualitative and quantitative sperm parameters. Nineteen patients were enrolled, the median age was 38 years (21–44 y). Serum AMH was correlated with increased FSH and T and decreased inhibin-B in gonadotoxic protocols (cisplatin or busulfan) and remained unchanged in nongonadotoxic protocols (capecitabine). AMH expression had the same pattern in mice serum and testes; it was negatively correlated with testicular/epididymal weight and sperm motility. The increase in testicular AMH expression was also correlated with elevated apoptosis (terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling) and reduced proliferation (Ki67, proliferating cell nuclear antigen; all seminiferous tubules cells were analyzed). Severely damaged mice testes demonstrated a marked costaining of AMH and GATA-4, a Sertoli cell marker; staining that resembled the pattern of the Sertoli cell-only condition. Our study indicates that the pattern of serum AMH expression, in combination with other hormones, can delineate testicular damage, as determined in both experimental settings. Future large-scale clinical studies are warranted to further define the role of AMH as a biomarker for testicular toxicity.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2015-1310
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2015
    detail.hit.zdb_id: 2011695-0
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  • 5
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    Online Resource
    miR-125a Induces HER2 Expression and Sensitivity to Trastuzumab in Triple-Negative Breast Cancer Lines
    Frontiers Media SA ; 2020
    In:  Frontiers in Oncology Vol. 10 ( 2020-2-28)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 10 ( 2020-2-28)
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    DOI: 10.3389/fonc.2020.00191
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2649216-7
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  • 6
    Online Resource
    Online Resource
    Doxorubicin-induced apoptosis in germinal vesicle (GV) oocytes☆
    Elsevier BV ; 2010
    In:  Reproductive Toxicology Vol. 30, No. 4 ( 2010-12), p. 566-572
    Details
    In: Reproductive Toxicology, Elsevier BV, Vol. 30, No. 4 ( 2010-12), p. 566-572
    Type of Medium: Online Resource
    ISSN: 0890-6238
    URL: Article
    DOI: 10.1016/j.reprotox.2010.07.003
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 2010593-9
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  • 7
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    Online Resource
    Dexrazoxane exacerbates doxorubicin-induced testicular toxicity
    Bioscientifica ; 2015
    In:  REPRODUCTION Vol. 150, No. 4 ( 2015-10), p. 357-366
    Details
    In: REPRODUCTION, Bioscientifica, Vol. 150, No. 4 ( 2015-10), p. 357-366
    Abstract: Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5 mg/kg DXR, 100 mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity.
    Type of Medium: Online Resource
    ISSN: 1470-1626 , 1741-7899
    URL: Article
    DOI: 10.1530/REP-15-0129
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2015
    detail.hit.zdb_id: 2037813-0
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  • 8
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    Online Resource
    Gonadotrophin-releasing hormone agonists for fertility preservation: unraveling the enigma?
    Oxford University Press (OUP) ; 2015
    In:  Human Reproduction Vol. 30, No. 5 ( 2015-05), p. 1089-1101
    Details
    In: Human Reproduction, Oxford University Press (OUP), Vol. 30, No. 5 ( 2015-05), p. 1089-1101
    Type of Medium: Online Resource
    ISSN: 1460-2350 , 0268-1161
    URL: Article
    DOI: 10.1093/humrep/dev037
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
    detail.hit.zdb_id: 1484864-8
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  • 9
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    Online Resource
    Cetuximab intensifies cisplatin-induced testicular toxicity
    Elsevier BV ; 2016
    In:  Reproductive BioMedicine Online Vol. 33, No. 1 ( 2016-07), p. 102-110
    Details
    In: Reproductive BioMedicine Online, Elsevier BV, Vol. 33, No. 1 ( 2016-07), p. 102-110
    Type of Medium: Online Resource
    ISSN: 1472-6483
    URL: Article
    DOI: 10.1016/j.rbmo.2016.04.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 2057455-1
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  • 10
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    Online Resource
    The impact of oxaliplatin on the gonads: From bench to bedside.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 3_suppl ( 2015-01-20), p. 584-584
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 3_suppl ( 2015-01-20), p. 584-584
    Abstract: 584 Background: Recent studies have indicated a significant increase of young colorectal cancer patients, who may then face unique survivorship issues as fertility concerns. The impact of oxaliplatin on gonadal function remains unclear. We prospectively evaluated oxaliplatin-induced gonadotoxicity in a cohort of young patients. In a preclinical setting, the impact of oxaliplatin on the gonads was prospectively studied in mice. Methods: Newly diagnosed female ( 〈 43 years) and male ( 〈 45 years) patients who were candidates for oxaliplatin-based protocol were enrolled into the study. Hormonal profile (including AMH and menstrual pattern) was measured in female patients and in male patients at baseline and within 6 months post-treatment. In the pre-clinical setting, pubertal mice (female and male cohorts) were injected with oxaliplatin or saline (control) and sacrificed at various time-points (1 week, 1 or 3 months) post-treatment. Ovarian reserve was estimated by serial serum AMH. Testicular function was evaluated by serial serum inhibin and sperm count. Gonads had been retrieved at each time point for immunohistochemical study of apoptosis (TUNEL, Ki67) and repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL). Results: Eighteen patients (10 women; 8 men) were enrolled. Median age for women was 34y (range 27-43) and for men 39y (33-44). AMH decreased in all women post-treatment, but was measurable in 8/10 patients (p 〈 0.05). FSH was elevated yet in the premenopausal range in these patients. Three patients remain menstruating during treatment. Additional five patients resumed menstruation within 6 months post-treatment. In female mice oxaliplatin induced moderate apoptosis at 1-month post treatment with a recovery of the histology compared with control mice at later time points. Inhibin was slightly decreased in men post-treatment. In male mice oxaliplatin exerted moderate apoptosis and transient decrease in spermatocyte staining in histological sections and a non-significant decrease in sperm count. Conclusions: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. Future prospective large-scale studies are warranted in order to affirm these outcomes.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.3_suppl.584
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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