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Effects of Paclitaxel and Cisplatin on Ovarian Reserves in Rats  [cached]
?a?da? Türky?lmaz,Bülent ?z?elik,Mahmut Tuncay ?zgün,Tolga Atakul
Erciyes Medical Journal , 2008,
Abstract: Purpose: We targeted to investigate the effects of paclitaxel and cisplatin treatments, both solely and in combination with each other, on ovarian reserves in rats. Materials and methods: Forty female Wistar albino rats were divided into 4 groups as to include 10 rats in each. While 7.5 mg/kg paclitaxel was given to group II, 5mg/kg cisplatin was administered to group III, 7.5 mg/kg paclitaxel and 5 mg/kg cisplatin combination therapy was applied to group IV via intraperitoneal route in a sterile way at single dose. Group I, which was assigned to be the control group, was subjected to intraperitoneal sterile saline in equal volumes. One week after the chemotherapy, ovaries of all the rats were oophorectomized. Hematoxylin-eosin stain was used to determine the follicles. Results: Number of primordial, primary, and secondary follicles were found to show a statistically significant decrease (p<0.001). Most significant drop in number of follicles was determined to be in group 4. Conclusion: Single and combined use of paclitaxel and cisplatin caused a decrease in number of primordial, primary, secondary, and tertiary follicles. Most significant drop regarding the number of follicles, was found to be in the combined chemotherapy group. Therefore, single-agent chemotherapy regimes may be considered as an alternative for patients asking for fertility.
Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum
Bohuslav Melichar, Radomír Hy?pler, Emanuela Dragounová, Josef Dvo?ák, Hana Kalábová, Alena Tichá
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-155
Abstract: Intestinal permeability was assessed in 36 breast and ovarian cancer patients treated with paclitaxel/platinum combination by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose and mannitol after oral challenge. The significance of differences during the therapy compared to pre-treatment values was studied by Wilcoxon paired test. The differences between groups of patient were studied by Mann-Whitney U test. Fisher exact test was used to compare the frequency in different subgroups.After administration of the first dose, a significant (p < 0.05) decrease in xylose absorption and increased lactulose/mannitol, sucrose/mannitol, lactulose/xylose and sucrose/xylose ratios were observed, but these parameters returned subsequently to pre-treatment levels. Patients who experienced serious (grade 3 or 4) toxicity had at baseline significantly lower percentages of xylose, mannitol and sucrose, and higher lactulose/mannitol ratio. Nine of 13 (69%) patients with baseline lactulose/mannitol ratio 0.070 or above experienced serious toxicity compared to 4 out of 23 patients (17%) with the ratio below 0.070 (p = 0.002). Post-treatment lactulose, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were significantly increased in patients with serious toxicity.A transient significant increase in lactulose/monosaccharide and sucrose/monosaccharide ratios was observed in ovarian and breast cancer patients treated with paclitaxel and platinum. Increased lactulose absorption, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were evident in patients with grade 3 or 4 toxicity, and increased baseline lactulose/mannitol ratio predicted serious toxicity.Combination of platinum derivatives (cisplatin or carboplatin) with paclitaxel is currently the standard front line regimen for patients with advanced epithelial ovarian carcinoma (EOC) after demonstration of superior survival in randomized clinical trials [1,2]. This combination is
Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy
Carlos D Gamarra-Luques, Alicia A Goyeneche, Maria B Hapon, Carlos M Telleria
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-200
Abstract: We established an in vitro approach wherein ovarian cancer cells with various sensitivities to cisplatin or paclitaxel were exposed to a round of lethal doses of cisplatin for 1?h plus paclitaxel for 3?h. Thereafter, cells were maintained in media with or without mifepristone, and short- and long-term cytotoxicity was assessed.Four days after treatment the lethality of cisplatin-paclitaxel was evidenced by reduced number of cells, increased hypodiploid DNA content, morphological features of apoptosis, DNA fragmentation, and cleavage of caspase-3, and of its downstream substrate PARP. Short-term presence of mifepristone either enhanced or did not modify such acute lethality. Seven days after receiving cisplatin-paclitaxel, cultures showed signs of relapse with escaping colonies that repopulated the plate in a time-dependent manner. Conversely, cultures exposed to cisplatin-paclitaxel followed by mifepristone not only did not display signs of repopulation following initial chemotherapy, but they also had their clonogenic capacity drastically reduced when compared to cells repopulating after cisplatin-paclitaxel.Cytostatic concentrations of mifepristone after exposure to lethal doses of cisplatin and paclitaxel in combination blocks repopulation of remnant cells surviving and escaping the cytotoxic drugs.Ovarian cancer is the most lethal gynecologic disease [1]. Because early detection biomarkers are not yet available and the symptomatology is vague, the disease is usually diagnosed at a late stage when growths have extended within the peritoneal cavity [2-4]. At this point, patients usually undergo cytoreductive surgery followed by platinum plus taxane-based chemotherapy [1,3]. The response to this regime is successful with disease remission in at least 70% of the cases; however, the majority of first responders will relapse within 18?months with a platinum-resistant disease [3-6]. Unfortunately, there is no current agreed maintenance therapy following the initial cis
No significant role for beta tubulin mutations and mismatch repair defects in ovarian cancer resistance to paclitaxel/cisplatin
Bárbara Mesquita, Isabel Veiga, Deolinda Pereira, Ana Tavares, Isabel M Pinto, Carla Pinto, Manuel R Teixeira, Sérgio Castedo
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-101
Abstract: Thirty-four patients with primary ovarian carcinomas (26 serous and eight clear cell carcinomas) treated with paclitaxel/cisplatin were analysed. TUBB exon 4 was analysed by nested PCR after a first round PCR using intronic primers. Microsatellite analysis was performed with the quasimonomorphic markers BAT 26 and BAT 34.Twenty-two of the 34 ovarian cancers (64.7%) presented residual tumour after surgery, seven of which (7/22; 31.8%) were shown to be chemoresistant (five serous and two clear cell tumours). Sequence analysis did not find any mutation in TUBB exon 4. Microsatellite instability was not detected in any of the ovarian carcinomas.We conclude that TUBB exon 4 mutations and mismatch repair defects do not play a significant role in paclitaxel/cisplatin resistance.Ovarian cancer is the fourth most common cancer in women [1]. The standard treatment for ovarian cancer is cytoreductive surgery followed by combination systemic chemotherapy [2]. Since the middle 90's, the combination paclitaxel/cisplatin became the standard chemotherapeutic treatment for poor prognosis ovarian cancer [3]. Nevertheless, some patients are resistant to this chemotherapeutic treatment, making it important to clarify the underlying mechanisms of resistance [4].Paclitaxel binds to microtubules and causes kinetic suppression (stabilisation) of microtubule dynamics, promoting their polymerisation and cell cycle arrest in mitosis (antimitotic activity), which probably leads to apoptosis [5,6]. Microtubules are composed of a dimeric protein, tubulin, with alpha (α) and beta (β) tubulin heterodimers in dynamic equilibrium. The β-tubulin gene (TUBB), mapped to 6p21.3 [7], is composed of four exons and encodes a 445-aminoacid protein with GTPase function to which paclitaxel preferentially binds [8]. Cisplatin is activated intracellularly and establishes inter- and intra-strand DNA adducts that block replication and translation. The fate of cells after cisplatin exposure depends both on the ext
Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin
Cheryl A Sherman-Baust, Kevin G Becker, William H Wood III, Yongqing Zhang, Patrice J Morin
Journal of Ovarian Research , 2011, DOI: 10.1186/1757-2215-4-21
Abstract: To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified changes in gene expression patterns using Illumina whole-genome expression microarrays. Validation of selected genes was performed by RT-PCR and immunoblotting. Pathway enrichment analysis using the KEGG, GO, and Reactome databases was performed to identify pathways that may be important in each drug resistance phenotype.A total of 845 genes (p < 0.01) were found altered in at least one drug resistance phenotype when compared to the parental, drug sensitive cell line. Focusing on each resistance phenotype individually, we identified 460, 366, and 337 genes significantly altered in cells resistant to cisplatin, doxorubicin, and paclitaxel, respectively. Of the 845 genes found altered, only 62 genes were simultaneously altered in all three resistance phenotypes. Using pathway analysis, we found many pathways enriched for each resistance phenotype, but some dominant pathways emerged. The dominant pathways included signaling from the cell surface and cell movement for cisplatin resistance, proteasome regulation and steroid biosynthesis for doxorubicin resistance, and control of translation and oxidative stress for paclitaxel resistance.Ovarian cancer cells develop drug resistance through different pathways depending on the drug used in the generation of chemoresistance. A better understanding of these mechanisms may lead to the development of novel strategies to circumvent the problem of drug resistance.In the United States, ovarian cancer represents 3% of all the new cancer cases in women, but accounts for 5% of all the cancer deaths [1]. This discrepancy is due, in part, to the common resistance of ovarian cancer to current chemotherapy regimens. The vast majority of ovarian cancer patients w
Resistance to Paclitaxel in a Cisplatin-Resistant Ovarian Cancer Cell Line Is Mediated by P-Glycoprotein  [PDF]
Britta Stordal, Marion Hamon, Victoria McEneaney, Sandra Roche, Jean-Pierre Gillet, John J. O’Leary, Michael Gottesman, Martin Clynes
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040717
Abstract: The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
The effect of the histone deacetylase inhibitor M344 on BRCA1 expression in breast and ovarian cancer cells
Johanne I Weberpals, Anna M O'Brien, Nima Niknejad, Kyla D Garbuio, Katherine V Clark-Knowles, Jim Dimitroulakos
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-29
Abstract: With the addition of M344, the platinum-sensitive breast and ovarian cancer cell lines that displayed relatively high BRCA1 protein levels demonstrated significant potentiation of cisplatin cytotoxicity in association with a reduction of BRCA1 protein. The cisplatin-resistant cell lines, T-47D and A2780s, elicited increased cytotoxicity of cisplatin with M344 and down regulation of BRCA1 protein levels. A2780s cells subjected to combination platinum and M344 treatment, demonstrated increased DNA damage as assessed by the presence of phosphorylated H2A.X foci in comparison to either treatment alone. Using Chromatin Immunoprecipitation, A2780s and MCF7 cells exposed to M344 alone and in combination with cisplatin, did not demonstrate enhanced acetylated Histone 4 at the BRCA1 promoter, suggesting an indirect effect on this promoter.The enhanced sensitivity of HDAC inhibition to platinum may be mediated through a BRCA1-dependent mechanism in breast and ovarian cancer cells. The findings of this study may be important in the future design of clinical trials involving HDAC inhibitors using BRCA1 as a tumour biomarker.Epithelial ovarian cancer (OC) is the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy [1]. In spite of aggressive surgical cytoreduction and combination platinum/paclitaxel chemotherapy, over 75% of women with stage III/IV disease will relapse and succumb to their disease. Resistance to platinum-based therapy is a primary obstacle in the management of advanced OC and novel therapies are required to enhance platinum chemotherapy and to improve prognosis. Hereditary mutations in the Breast Cancer 1 (BRCA1) tumor suppressor gene are associated with a significant risk of developing breast and OC [2,3]. Although somatic mutations in BRCA1 are uncommon in sporadic OC, BRCA1 dysfunction is frequently observed [4]. Silencing of BRCA1, through promoter methylation, decreased expression through gene deletion (loss of heterozygos
Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer  [cached]
Francesco Di Costanzo,Silvia Gasperoni,Virginia Rotella,Federica Di Costanzo
OncoTargets and Therapy , 2009,
Abstract: Francesco Di Costanzo,1 Silvia Gasperoni,1 Virginia Rotella,1 Federica Di Costanzo21Struttura Complessa Oncologia Medica, Azienda Ospedaliero Universitaria Careggi, Florence; 2Servizio di Oncologia: Ospedale S: Maria della Stella, Orvieto, ItalyAbstract: Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL (CrEL) and Tween 80 respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane ), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.Keywords: breast cancer, nab-paclitaxel, chemotherapy
Combination Therapy of Albumin-Bound Paclitaxel and Carboplatin as First Line Therapy in a Patient with Ovarian Cancer  [PDF]
K. N Srinivasan,Amit Rauthan,R. Gopal
Case Reports in Oncological Medicine , 2014, DOI: 10.1155/2014/940591
Abstract: Background. Ovarian cancer is the ninth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Albumin-bound paclitaxel is known to increase intratumoral concentration of the paclitaxel by a receptor-mediated transport process across the endothelial cell wall, thereby breaching the blood/tumor interface. We present below three cases in which nab-paclitaxel based chemotherapy has been used in different settings for patients with ovarian cancer. Case Presentation. In the first case nab-paclitaxel was used along with carboplatin in adjuvant setting, in the second case, nab-paclitaxel was used along with carboplatin and bevacizumab as second line chemotherapy in a relapsed ovarian cancer case, and the third case delineates the use of nab-paclitaxel along with cisplatin as third line chemotherapy. Conclusion. In all the three scenarios, patients tolerated the chemotherapy well, as well as responding well to nab-paclitaxel based chemotherapy. The patients are currently on long-term follow-up and have been having an uneventful postchemotherapy. 1. Introduction Ovarian cancer is the ninth most common cancer in women (excluding skin cancer). It ranks fifth among the causes of cancer related deaths in women worldwide. A woman’s risk of getting invasive ovarian cancer in her lifetime is about one in 71 and the lifetime risk of dying from invasive ovarian cancer is about one in 95 [1]. However, there are large variations in the incidence of ovarian cancer in different areas across the world. In India, ovarian cancer is emerging as one of the most common malignancies affecting women according to the cancer registries [2]. It is one of the most lethal gynecologic diseases and lacks early detection through screening tests. The symptomatology is not very clear and, as a result, the disease is usually diagnosed at a later stage when growth has extended within the peritoneal cavity [3]. Carboplatin in combination with paclitaxel has been broadly accepted as first-line chemotherapy for advanced epithelial ovarian cancer [4]. Albumin-bound paclitaxel is known to increase intratumoral concentration of paclitaxel by a receptor-mediated transport process across the endothelial cell wall, thereby breaching the blood/tumor interface [5]. Teneriello et al. [6] have shown albumin-paclitaxel to be highly active as a single agent in patients with platinum-sensitive recurrent ovarian cancer. Albumin-bound paclitaxel is administered with 100?mL normal saline with no premedications as compared to the regular paclitaxel which required
Kaempferol enhances cisplatin's effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc
Haitao Luo, Matthew K Daddysman, Gary O Rankin, Bing-Hua Jiang, Yi C Chen
Cancer Cell International , 2010, DOI: 10.1186/1475-2867-10-16
Abstract: Ten chemicals were screened for sensitizing OVCAR-3 ovarian cancer cell growth in response to cisplatin treatment. For kaempferol, which shows a significant synergistic interaction with cisplatin, expression of ABCC1, ABCC5, ABCC6, NFkB1, cMyc, and CDKN1A genes was further examined. For cisplatin/kaempferol treatments on OVCAR-3 cancer cells, the mRNA levels of ABCC1, ABCC5, and NFkB1 did not change. However, significant inhibition of ABCC6 and cMyc mRNA levels was observed for the cisplatin/kaempferol combined treatment. The CDKN1A mRNA levels were significantly up-regulated by cisplatin/kaempferol treatment. A plot of CDKN1A mRNA levels against that of cMyc gene further revealed a reverse, linear relationship, proving cMyc's regulation on CDKN1A gene expressions. Our work found that kaempferol works synergistically with cisplatin in inhibiting ovarian cancer cell viability, and their inhibition on cell viabilities was induced through inhibiting ABCC6 and cMyc gene transcription. Apoptosis assay showed the addition of 20 μM kaempferol to the cisplatin treatment induces the apoptosis of the cancer cells.Kaempferol enhances the effect of cisplatin through down regulation of cMyc in promoting apoptosis of ovarian cancer cells. As a dietary component, kaempferol sensitizes ovarian cancer cells to cisplatin treatment and deserves further studies for possible applications in chemotherapy of ovarian cancers.Ovarian cancer is one of the most important diseases for women in Western countries. It is the fifth leading cause of cancer-related deaths [1]. Treatment of ovarian cancers usually involves surgery and chemotherapy. The combination of cisplatin and paclitaxel as a chemotherapeutic regimen has improved the survival of ovarian cancer patients. However, the results are not satisfying because of drug resistance developed by cancer cells [2]. The cancer frequently progresses after the treatment and the majority of ovarian cancer patients die as cancer later relapses [3]. T
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