Intraperitoneal Dose Of Cisplatin Research Articles

Potential ameliorative effects of bilberry (Vaccinium myrtillus L.) fruit extract on cisplatin-induced reproductive damage in adult male albino rats.

Cisplatin (CP) is a widely used chemotherapeutic agent, but its severe side effects impact testicular function. We investigated the potential protective effects of bilberry extract against CP-induced testicular toxicity. Forty adult male albino rats were divided into four groups. Control animals received a single oral dose of 0.9% saline. Bilberry-treated rats received oral bilberry extract (200 mg/kg body weight [BW] dissolved in 1 mL of saline) daily for 10 consecutive days. CP-treated animals were administered a single intraperitoneal dose (7.5 mg/kg BW). Finally, a bilberry+CP group received oral bilberry extract (200 mg/kg BW) daily for 10 consecutive days, with one intraperitoneal dose of CP (7.5 mg/kg BW) on day 2. We assessed sperm count, motility, viability, and abnormalities, along with testis weight, testis weight-to-BW ratio, antioxidant activity, levels of oxidative stress markers (malondialdehyde [MDA] and hydrogen peroxide [H2O2]), sex hormones (follicle-stimulating hormone [FSH], luteinizing hormone [LH], and testosterone), and apoptotic and anti-apoptotic markers, and DNA damage. Testicular tissue underwent histopathological examination. Among CP-treated rats, significantly lower values were observed for testis weight; testis weight-to-BW ratio; levels of FSH, LH, testosterone, superoxide dismutase, catalase, glutathione S-transferase, glutathione, and B-cell lymphoma 2; and sperm count, motility, and proportion of normal sperm. CP administration was associated with higher MDA, H2O2, p53, Bax, cytochrome c, caspase 9, and caspase 3 levels, along with elevated tail moment. However, bilberry extract administration significantly improved all altered parameters. Bilberry treatment demonstrated protective effects and reduced CP-induced testicular toxicity via antioxidant activity and cytoprotection.

Coenzyme Q10 Attenuates Cisplatin-induced Nephrotoxicity Through Counteracting Oxidative Stress and Inflammation

Background: Cisplatin is an anticancer drug used in the management of solid tumors, however, dose-related nephrotoxicity is one of its major problems. Agents having antioxidants, antiinflammatory and/or antiapoptotic activities may thus represent potential therapeutic options to avoid cisplatin-induced nephrotoxicity. Among these agents, coenzyme Q10 has several pharmacological properties including antioxidant, anti-inflammatory and/or anti-apoptotic effects. Objective: The current study aimed to examine whether coenzyme Q10 could attenuate cisplatininduced nephrotoxicity or not. Methods: 24 adult rats were randomly separated into three groups (8 rats per group). The first one was the control group, rats receiving vehicle (olive oil) intraperitoneally. The second group was Cisplatin treated group, rats were receiving 13 mg/kg of Cisplatin intraperitoneally as a single dose. The third group (Cisplatin + Coenzyme Q10), rats were receiving 13 mg/kg as a single intraperitoneal dose of Cisplatin and coenzyme Q10 daily for six consecutive days (10 mg/kg intraperitoneally). Results: Cisplatin caused significant increases in serum creatinine and severe histological lesions. Cisplatin treated group also showed a significant elevation in renal malondialdehyde concentration as a marker of oxidative stress; renal tumor necrosis factor-alpha concentration as a marker of inflammation; and Kidney injury molecule -1 concentration. Coenzyme Q10 significantly attenuated cisplatininduced nephrotoxicity through lowering serum creatinine and improving nephrotoxicity histological scores. Coenzyme Q10 also significantly reduced the renal concentration of MDA, TNF-α and KIM-1 relative to cisplatin treated group. Conclusions: Coenzyme Q10 has a potential nephroprotective effect against cisplatin-induced nephrotoxicity that was demonstrated by biochemical and histopathological analysis.

Abstract 1586: Oral administration of HIV-protease inhibitors reduces ovarian tumor growth in vivo

Abstract INTRODUCTION: Ritonavir boosted lopinavir (LPV/r) is an FDA approved HIV-protease inhibitor combination that is a well tolerated and preferred treatment for HIV patients. Ritonavir is a potent irreversible inhibitor of cytochrome P450 isoform 3A (CYP3A) which can substantially increase bioavailability of lopinavir in vivo. This combination of lopinavir and ritonavir has been shown to increase the efficacy of reducing viral load in AIDS patients. HIV patients taking antiretroviral protease inhibitors such as LPV/r have a lower incidence of HIV associated malignancies such as non-Hodgkin's lymphoma, cervical cancer and Kaposi's sarcoma, leading to the hypothesis that these drugs have antineoplastic activity. Given the need for novel treatment approaches in ovarian cancer, we are investigating the antineoplastic effects of LPV/r, in vivo. METHODS: A xenograph model of ovarian cancer is used to assess the antineoplastic effect of LPV/r in vivo. Oral doses of LPV/r dissolved in corn oil are administered to mice over the course of 2-3 weeks. Tumor area and mouse weight are monitored. After 2-3 weeks tumors are harvested and analyzed. RESULTS: Preliminary results indicate that LPV/r administered orally in combination with a high fat diet inhibits tumor growth in vivo without inducing weight loss. In contrast, the dose of intraperitoneal cisplatin required to attain a similar antineoplastic effect resulted in significant weight loss and morbidity. CONCLUSIONS: Because protease inhibitors can induce both apoptotic and non-apoptotic ovarian cancer cell death in vitro and in vivo, these drugs may circumvent chemoresistance due to alterations in apoptotic response. Our data suggests that LPV/r may also have clinical application in the treatment of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1586. doi:10.1158/1538-7445.AM2011-1586

Abstract 3259: HIV protease inhibitors induce apoptotic and non-apoptotic cell death in ovarian cancer cells in vitro and in vivo

Abstract Introduction: HIV patients taking antiretroviral protease inhibitors have a lower incidence of HIV associated malignancies, leading to the hypothesis that these drugs have antineoplastic activity. Given the need for novel treatment approaches in ovarian cancer, we investigated the antineoplastic effects of the HIV protease inhibitors saquinavir and nelfinavir in vitro and in vivo. Methods: A panel of ovarian cancer cell lines was treated with saquinavir and nelfinavir. The effect of protease inhibitors on cell growth, viability, apoptotic and non-apoptotic cell death was determined. Stimulation of endoplasmic reticulum stress (ERS) response was assessed by immunoblotting for ERS regulators GRP78 and ATF6. Induction of autophagy was assessed using transmission electron microscopy (TEM), and confocal microscopy was performed to demonstrate changes in green fluorescent protein-labeled LC3 expression patterns. A xenograph model of ovarian cancer was used to assess the antineoplastic effect of nelfinavir in vivo. Results: HIV protease inhibitors induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Treatment with protease inhibitors resulted in caspase-dependent apoptosis and caspase-independent cell death characterized by induction of ERS and autophagy. Cellular morphology assessed by TEM revealed apoptotic, autophagic, and necrotic cell death. Preliminary results indicate that nelfinavir administer intraperitoneally inhibits tumor growth in vivo without inducing weight loss. In contrast, the dose of intraperitoneal cisplatin required to attain a similar antineoplastic effect resulted in significant weight loss and morbidity. Conclusions: Because protease inhibitors can induce both apoptotic and non-apoptotic cell death, these drugs may circumvent chemoresistance due to alterations in apoptotic response. Saquinavir and Nelfinavir are FDA-approved agents for the treatment of HIV, and our data suggest that these drugs may also have clinical application in the treatment of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3259.

Cisplatin augments cytotoxic T-lymphocyte–mediated antitumor immunity in poorly immunogenic murine lung cancer

Objective Many tumors are poorly immunogenic and resistant to cytotoxic T-lymphocyte–mediated cell lysis. Because cisplatin has been demonstrated to increase tumor cell Fas receptor expression, we hypothesized that cisplatin will enhance cytotoxic T-lymphocyte tumor cell killing and augment the antitumor effect of an active immunotherapy strategy in a poorly immunogenic murine lung cancer model. Methods Lewis lung carcinoma cells were exposed to cisplatin in vitro, and Fas receptor expression and apoptosis in response to an agonistic anti-Fas antibody were quantified using flow cytometry. Wild-type and Fas ligand–deficient mice bearing Lewis lung carcinoma flank tumors were then treated with intraperitoneal cisplatin as well as an intratumoral injection of an adenovirus gene transfer vector encoding CD40 ligand. End points included tumor size, animal survival, and Fas expression (determined using immunofluorescence). Cytotoxicity assays were performed using splenocytes from adenovirus gene transfer vector encoding CD40 ligand–treated animals as effectors and cisplatin-treated Lewis lung carcinoma cells as targets. Results Cisplatin induced heightened expression of Fas receptor on Lewis lung carcinoma cells in vitro and in vivo and enhanced apoptosis in cells exposed to an agonistic anti-Fas antibody. In vivo, the combination of 1 dose of intraperitoneal cisplatin and intratumoral adenovirus gene transfer vector encoding CD40 ligand inhibited tumor growth and prolonged survival compared with adenovirus gene transfer vector encoding CD40 ligand alone, resulting in a higher cure rate. This effect was lost in Fas ligand–deficient mice. Splenocytes from adenovirus gene transfer vector encoding CD40 ligand–treated wild-type mice lysed cisplatin-treated Lewis lung carcinoma cells more efficiently than untreated Lewis lung carcinoma cells, an effect lost in splenocytes from Fas ligand–deficient mice. Conclusion Cisplatin augments the antitumor effect of a cytotoxic T-lymphocyte–mediated immunotherapy strategy, resulting in a higher cure rate than seen with immunotherapy alone. This effect is associated with the enhanced ability of cytotoxic T lymphocytes to lyse tumor cells that have been exposed to cisplatin through Fas/Fas ligand interactions.

Prognostic results of cisplatin IP and carboplatin IV with G-CSF in patients with ovarian cancer.

We performed a dose-escalation study of carboplatin combined with a fixed dose of intraperitoneal cisplatin and G-CSF in patients with epithelial ovarian cancer, and analyzed the progression-free and overall survival. Six of the patients who entered the study with stage IC and II disease are still alive with no evidence of disease. The five-year survival rate was 61% for the 18 patients with stage III and IV disease; progression-free survival over 5 years was 32%. Our results show this to be an effective treatment regimen for epithelial ovarian cancer. Prognosis is good with this combined carboplatin/cisplatin/G-CSF therapy, especially for those patients with microscopic or no residual disease.