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Amit Maity - One of the best experts on this subject based on the ideXlab platform.
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a phase i trial of the hiv protease inhibitor Nelfinavir with concurrent chemoradiotherapy for unresectable stage iiia iiib non small cell lung cancer a report of toxicities and clinical response
Journal of Thoracic Oncology, 2012Co-Authors: Ramesh Rengan, Amit Maity, Rosemarie Mick, Daniel A Pryma, Mark A Rosen, Lilie L Lin, Tracey L Evans, James P Stevenson, Corey J Langer, John C KucharczukAbstract:Background The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC). Methods Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis. Results Sixteen patients were enrolled and 13 patients received at least one dose of Nelfinavir. Twelve patients were treated with Nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of Nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%). Conclusion Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that Nelfinavir has promising activity in this disease.
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Phosphatase and Tensin Homologue Deficiency in Glioblastoma Confers Resistance to Radiation and Temozolomide that Is Reversed by the Protease Inhibitor Nelfinavir
Cancer research, 2007Co-Authors: Zibin Jiang, Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Eric J. Bernhard, Stephen M. Hahn, Rosemarie Mick, Maria Magdelena Georgescu, Amit MaityAbstract:Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by Nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as Nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the Nelfinavir acts along the Akt pathway to radiosensitize cells. However, Nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm 3 in the radiation + Nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, Nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and Nelfinavir. ( P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of Nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas. [Cancer Res 2007;67(9):4467–72]
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phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor Nelfinavir
Cancer Research, 2007Co-Authors: Zibin Jiang, Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Eric J. Bernhard, Stephen M. Hahn, Rosemarie Mick, Maria Magdelena Georgescu, Amit MaityAbstract:Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by Nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as Nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the Nelfinavir acts along the Akt pathway to radiosensitize cells. However, Nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm(3) in the radiation + Nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, Nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and Nelfinavir. (P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of Nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas.
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hiv protease inhibitors decrease vegf hif 1α expression and angiogenesis in glioblastoma cells
Neoplasia, 2006Co-Authors: Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Amit MaityAbstract:Abstract Glioblastomas are malignant brain tumors that are rarely curable, even with aggressive therapy (surgery, chemotherapy, radiation). Glioblastomas frequently display loss of PTEN and/or epidermal growth factor receptor activation, both of which activate the PI3K pathway. This pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α expression. We examined the effects of two human immunodeficiency virus protease inhibitors, Nelfinavir and amprenavir, which inhibit Akt signaling, on VEGF and HIF-1α expression and on angiogenesis. Nelfinavir decreased VEGF mRNA expression and VEGF secretion under normoxia. Downregulation of P-Akt decreased VEGF secretion in a manner similar to that of Nelfinavir, but the combination of the two had no greater effect, consistent with the idea that Nelfinavir decreases VEGF through the PI3K/ Akt pathway. Nelfinavir also decreased the hypoxic induction of VEGF and the hypoxic induction of HIF-1α which regulates VEGF promoter. The effect of Nelfinavir on HIF-1α was most likely mediated by decreased protein translation. Nelfinavir's effect on VEGF expression had the functional consequence of decreasing angiogenesis in in vivo Matrigel plug assays. Similar effects on VEGF and HIF-1α expression were seen with a different protease inhibitor, amprenavir. Our results support further research into these protease inhibitors for use in future clinical trials for patients with glioblastoma multiformes.
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Nelfinavir Down-regulates Hypoxia-Inducible Factor 1α and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy
Cancer research, 2006Co-Authors: Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Zibin Jiang, Eric J. Bernhard, Sydney M. Evans, Cameron J. Koch, Stephen M. Hahn, Amit MaityAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) expression. We examined the effect of Nelfinavir, an HIV protease inhibitor that inhibits Akt signaling, on VEGF and HIF-1alpha expression and on angiogenesis, tumor oxygenation, and radiosensitization. Nelfinavir decreases VEGF expression under normoxia via the transcription factor Sp1, which regulates the proximal core VEGF promoter. Nelfinavir decreased Sp1 phosphorylation and decreased Sp1 binding to a probe corresponding to the proximal VEGF promoter in a gel shift assay. Nelfinavir also decreased the hypoxic induction of HIF-1alpha, which also regulates the VEGF promoter, most likely by decreasing its translation. The effect of Nelfinavir on VEGF expression had the functional consequence of decreasing angiogenesis in an in vivo Matrigel plug assay. To determine the effect this might have on tumor radiosensitization, we did tumor regrowth assays with xenografts in nude mice. The combination of Nelfinavir and radiation increased time to regrowth compared with radiation alone whereas Nelfinavir alone had little effect on tumor regrowth. This radiosensitizing effect was greater than suggested by in vitro clonogenic survival assays. One possible explanation for the discordance is that Nelfinavir has an effect on tumor oxygenation. Therefore, we examined this with the hypoxia marker EF5 and found that Nelfinavir leads to increased oxygenation within tumor xenografts. Our results suggest that Nelfinavir decreases HIF-1alpha/VEGF expression and tumor hypoxia, which could play a role in its in vivo radiosensitizing effect. These data support the use of Nelfinavir in combination with radiation in future clinical trials.
David M. Burger - One of the best experts on this subject based on the ideXlab platform.
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The effect of the CYP2C19*2 heterozygote genotype on the pharmacokinetics of Nelfinavir
British journal of clinical pharmacology, 2006Co-Authors: David M. Burger, E. P. H. Colbers, H. Reinier Schwietert, Mark BeckerAbstract:Nelfinavir is the only currently licensed HIV-protease inhibitor that has an active metabolite present in potentially therapeutic concentrations. This metabolite, Nelfinavir hydroxyl-t-butylamide (also known as M8 or AG1402), is the product of enzymatic conversion of Nelfinavir by cytochrome P450 2C19 (CYP2C19) [1]. Previous studies have demonstrated that inherited (the homozygote’s CYP2C19*2 allele) and acquired (severe liver disease) deficiency of CYP2C19 result in diminished formation of M8 [2, 3].
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Effect of efavirenz treatment on the pharmacokinetics of Nelfinavir boosted by ritonavir in healthy volunteers.
British journal of clinical pharmacology, 2004Co-Authors: C.j.l. La Porte, Peter P. Koopmans, Yechiel A. Hekster, M. J. A. De Graaff‐teulen, E. P. H. Colbers, D. S. Voncken, S. Marco Ibanez, David M. BurgerAbstract:AIMS: A once-daily (q.d.) nucleoside-sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once-daily Nelfinavir/ritonavir was evaluated in healthy subjects. METHODS: This was a multiple-dose, open-label, single-group, two-period study in 24 healthy subjects. Each received from days 1-10 (period 1): 1875 mg Nelfinavir plus 200 mg ritonavir q.d. with a 300-kcal snack. During days 11-20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High-performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: All subjects completed the study. After the first period mean Nelfinavir AUC(0-24 h), C(max) and C(24) were 49.6 mg h(-1) l(-1), 5.0 mg l(-1) and 0.37 mg l(-1), and the sum of Nelfinavir plus its active metabolite M8 C(24) was 0.83 mg l(-1). The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for Nelfinavir AUC(0-24 h), C(max) and C(24) of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of Nelfinavir and M8 C(24) in period 2 was 0.99 mg l(-1), an increase of 19%. No serious adverse events occurred. CONCLUSIONS: The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C(24) concentration for Nelfinavir, and the sum of Nelfinavir and M8 C(24) concentrations was 0.99 mg l(-1). Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and Nelfinavir.
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Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of Nelfinavir and low-dose ritonavir in healthy volunteers.
British journal of clinical pharmacology, 2003Co-Authors: Rob E. Aarnoutse, Peter P. Koopmans, Yechiel A. Hekster, Peter Reiss, Jacqueline A. H. Droste, J. J. G. Van Oosterhout, M. Popescu, David M. BurgerAbstract:This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of Nelfinavir and low-dose ritonavir. Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of Nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for Nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of Nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) Nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of Nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than Nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for Nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of Nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of Nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of Nelfinavir and Nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of Nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). Administration of Nelfinavir in a once-daily regimen appears feasible. A Nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily Nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.
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treatment failure of Nelfinavir containing triple therapy can largely be explained by low Nelfinavir plasma concentrations
Therapeutic Drug Monitoring, 2003Co-Authors: David M. Burger, P.w.h. Hugen, Rob E. Aarnoutse, Richard M W Hoetelmans, Marielle Jambroes, Pythia T Nieuwkerk, Gerrit Schreij, Margriet M E Schneider, Marchina E Van Der Ende, Joep M A LangeAbstract:The relationship between plasma concentrations of Nelfinavir and virologic treatment failure was investigated to determine the minimum effective concentration of Nelfinavir. Plasma samples were prospectively collected from treatment-naive patients who began taking Nelfinavir, 1,250 mg BID + two nucleoside reverse transcription inhibitors (NRTIs). Nelfinavir concentration ratios were calculated by dividing each individual Nelfinavir level by the time-adjusted population value. Virologic failure was defined as either no response (a detectable viral load after 6 months) or a relapse (detectable viral load after being undetectable, or an increase in viral load >1 log above nadir). Forty-eight patients were included with a median follow-up period of 8 months. The median concentration ratio of Nelfinavir was 0.98 (interquartile range, 0.76-1.47). Virologic failure was observed in 29% of the patients. In a univariate analysis, the Nelfinavir concentration ratio appeared to be the single determinant that was related to virologic failure (P = 0.039). Patients with a median ratio <0.90 had a relative risk of 3.0 (95% CI, 1.2-7.6) for virologic failure. Using this threshold, virologic failures were detected with 64% sensitivity and 74% specificity (P = 0.014). Virologic failure of Nelfinavir-containing triple therapy can be explained, to a large extent, by low plasma levels of Nelfinavir.
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Pharmacokinetics of Nelfinavir in children: influencing factors and dose implications.
Antiviral therapy, 2003Co-Authors: Alina S. Bergshoeff, Pieter L. A. Fraaij, Annemarie M. C. Van Rossum, Tom F. W. Wolfs, Sibyl P. M. Geelen, Ronald De Groot, David M. BurgerAbstract:OBJECTIVES: The study describes the pharmacokinetics (PK) of the protease inhibitor Nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on Nelfinavir plasma levels. METHODS: HIV-1-infected children treated with Nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated. RESULTS: Twenty-four children (median age: 4.5 years, median Nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of Nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight. CONCLUSION: Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low Nelfinavir levels. These data show that the Nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of Nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing Nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for Nelfinavir in children.
Nabendu Pore - One of the best experts on this subject based on the ideXlab platform.
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Phosphatase and Tensin Homologue Deficiency in Glioblastoma Confers Resistance to Radiation and Temozolomide that Is Reversed by the Protease Inhibitor Nelfinavir
Cancer research, 2007Co-Authors: Zibin Jiang, Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Eric J. Bernhard, Stephen M. Hahn, Rosemarie Mick, Maria Magdelena Georgescu, Amit MaityAbstract:Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by Nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as Nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the Nelfinavir acts along the Akt pathway to radiosensitize cells. However, Nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm 3 in the radiation + Nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, Nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and Nelfinavir. ( P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of Nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas. [Cancer Res 2007;67(9):4467–72]
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phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor Nelfinavir
Cancer Research, 2007Co-Authors: Zibin Jiang, Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Eric J. Bernhard, Stephen M. Hahn, Rosemarie Mick, Maria Magdelena Georgescu, Amit MaityAbstract:Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by Nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as Nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the Nelfinavir acts along the Akt pathway to radiosensitize cells. However, Nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm(3) in the radiation + Nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, Nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and Nelfinavir. (P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of Nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas.
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hiv protease inhibitors decrease vegf hif 1α expression and angiogenesis in glioblastoma cells
Neoplasia, 2006Co-Authors: Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Amit MaityAbstract:Abstract Glioblastomas are malignant brain tumors that are rarely curable, even with aggressive therapy (surgery, chemotherapy, radiation). Glioblastomas frequently display loss of PTEN and/or epidermal growth factor receptor activation, both of which activate the PI3K pathway. This pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α expression. We examined the effects of two human immunodeficiency virus protease inhibitors, Nelfinavir and amprenavir, which inhibit Akt signaling, on VEGF and HIF-1α expression and on angiogenesis. Nelfinavir decreased VEGF mRNA expression and VEGF secretion under normoxia. Downregulation of P-Akt decreased VEGF secretion in a manner similar to that of Nelfinavir, but the combination of the two had no greater effect, consistent with the idea that Nelfinavir decreases VEGF through the PI3K/ Akt pathway. Nelfinavir also decreased the hypoxic induction of VEGF and the hypoxic induction of HIF-1α which regulates VEGF promoter. The effect of Nelfinavir on HIF-1α was most likely mediated by decreased protein translation. Nelfinavir's effect on VEGF expression had the functional consequence of decreasing angiogenesis in in vivo Matrigel plug assays. Similar effects on VEGF and HIF-1α expression were seen with a different protease inhibitor, amprenavir. Our results support further research into these protease inhibitors for use in future clinical trials for patients with glioblastoma multiformes.
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Nelfinavir Down-regulates Hypoxia-Inducible Factor 1α and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy
Cancer research, 2006Co-Authors: Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Zibin Jiang, Eric J. Bernhard, Sydney M. Evans, Cameron J. Koch, Stephen M. Hahn, Amit MaityAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) expression. We examined the effect of Nelfinavir, an HIV protease inhibitor that inhibits Akt signaling, on VEGF and HIF-1alpha expression and on angiogenesis, tumor oxygenation, and radiosensitization. Nelfinavir decreases VEGF expression under normoxia via the transcription factor Sp1, which regulates the proximal core VEGF promoter. Nelfinavir decreased Sp1 phosphorylation and decreased Sp1 binding to a probe corresponding to the proximal VEGF promoter in a gel shift assay. Nelfinavir also decreased the hypoxic induction of HIF-1alpha, which also regulates the VEGF promoter, most likely by decreasing its translation. The effect of Nelfinavir on VEGF expression had the functional consequence of decreasing angiogenesis in an in vivo Matrigel plug assay. To determine the effect this might have on tumor radiosensitization, we did tumor regrowth assays with xenografts in nude mice. The combination of Nelfinavir and radiation increased time to regrowth compared with radiation alone whereas Nelfinavir alone had little effect on tumor regrowth. This radiosensitizing effect was greater than suggested by in vitro clonogenic survival assays. One possible explanation for the discordance is that Nelfinavir has an effect on tumor oxygenation. Therefore, we examined this with the hypoxia marker EF5 and found that Nelfinavir leads to increased oxygenation within tumor xenografts. Our results suggest that Nelfinavir decreases HIF-1alpha/VEGF expression and tumor hypoxia, which could play a role in its in vivo radiosensitizing effect. These data support the use of Nelfinavir in combination with radiation in future clinical trials.
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Nelfinavir down regulates hypoxia inducible factor 1α and vegf expression and increases tumor oxygenation implications for radiotherapy
Cancer Research, 2006Co-Authors: Nabendu Pore, Anjali K. Gupta, George J. Cerniglia, Zibin Jiang, Eric J. Bernhard, Sydney M. Evans, Cameron J. Koch, Stephen M. Hahn, Amit MaityAbstract:The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) expression. We examined the effect of Nelfinavir, an HIV protease inhibitor that inhibits Akt signaling, on VEGF and HIF-1α expression and on angiogenesis, tumor oxygenation, and radiosensitization. Nelfinavir decreases VEGF expression under normoxia via the transcription factor Sp1, which regulates the proximal core VEGF promoter. Nelfinavir decreased Sp1 phosphorylation and decreased Sp1 binding to a probe corresponding to the proximal VEGF promoter in a gel shift assay. Nelfinavir also decreased the hypoxic induction of HIF-1α, which also regulates the VEGF promoter, most likely by decreasing its translation. The effect of Nelfinavir on VEGF expression had the functional consequence of decreasing angiogenesis in an in vivo Matrigel plug assay. To determine the effect this might have on tumor radiosensitization, we did tumor regrowth assays with xenografts in nude mice. The combination of Nelfinavir and radiation increased time to regrowth compared with radiation alone whereas Nelfinavir alone had little effect on tumor regrowth. This radiosensitizing effect was greater than suggested by in vitro clonogenic survival assays. One possible explanation for the discordance is that Nelfinavir has an effect on tumor oxygenation. Therefore, we examined this with the hypoxia marker EF5 and found that Nelfinavir leads to increased oxygenation within tumor xenografts. Our results suggest that Nelfinavir decreases HIF-1α/VEGF expression and tumor hypoxia, which could play a role in its in vivo radiosensitizing effect. These data support the use of Nelfinavir in combination with radiation in future clinical trials. (Cancer Res 2006; 66(18): 9252-9)
Joell J Gills - One of the best experts on this subject based on the ideXlab platform.
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a phase i trial of the hiv protease inhibitor Nelfinavir in adults with solid tumors
Oncotarget, 2014Co-Authors: Gideon M. Blumenthal, Joell J Gills, Marc S. Ballas, Wendy B. Bernstein, Takefumi Komiya, Roopa Dechowdhury, Betsy Morrow, Hyejeong Root, Guinevere Chun, Cynthia HelsabeckAbstract:// Gideon M. Blumenthal 1 , Joell J. Gills 3 , Marc S. Ballas 1 , Wendy B. Bernstein 1 , Takefumi Komiya 1 , Roopa Dechowdhury 1 , Betsy Morrow 1 , Hyejeong Root 1 , Guinevere Chun 1 , Cynthia Helsabeck 1 , Seth M. Steinberg 2 , Jaclyn LoPiccolo 1 , Shigeru Kawabata 3 , Erin R. Gardner 1 , William D. Figg 1 , Phillip A. Dennis 3 1 Medical Oncology Branch, National Cancer Institute, Bethesda, MD 2 Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 3 Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA Correspondence to: Phillip A. Dennis, e-mail: pdennis@jhmi.edu Key words: Nelfinavir, phase I clinical trial, AKT, endoplasmic reticulum stress, neuroendocrine Received: June 30, 2014 Accepted: August 28, 2014 Published: September 05, 2014 ABSTRACT Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of Nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of Nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral Nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, Nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
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A phase I trial of the HIV protease inhibitor Nelfinavir in adults with solid tumors
Oncotarget, 2014Co-Authors: Gideon M. Blumenthal, Joell J Gills, Marc S. Ballas, Wendy B. Bernstein, Takefumi Komiya, Roopa Dechowdhury, Betsy Morrow, Hyejeong Root, Guinevere Chun, Cynthia HelsabeckAbstract:Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of Nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of Nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral Nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, Nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
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Nelfinavir a new anti cancer drug with pleiotropic effects and many paths to autophagy
Autophagy, 2008Co-Authors: Joell J Gills, Jaclyn Lopiccolo, Phillip A DennisAbstract:The development of cancer drugs is slow and costly. One approach to accelerate the availability of new drugs is to reposition drugs approved for other indications as anti-cancer agents. HIV protease inhibitors (HIV PIs) are useful in treating HIV infection and cause toxicities in humans that are similar to those observed when the kinase Akt, a target for cancer therapy, is inhibited. To test whether HIV PIs inhibited Akt and cancer cell proliferation, we screened 6 HIV PIs and found that three, ritonavir, saquinavir and Nelfinavir, inhibit the growth of over 60 cancer cell lines derived from 9 different tumor types; Nelfinavir is the most potent. Nelfinavir causes caspase-dependent apoptosis and non-apoptotic death, as well as endoplasmic reticulum (ER) stress and autophagy. Nelfinavir blocks growth factor receptor activation and decreases growth factor-induced and endogenous Akt signaling. In vivo, Nelfinavir inhibits tumor growth and upregulates markers of ER stress, autophagy and apoptosis. Nelfinavir ...
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Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy.
Autophagy, 2007Co-Authors: Joell J Gills, Jaclyn Lopiccolo, Phillip A DennisAbstract:The development of cancer drugs is slow and costly. One approach to accelerate the availability of new drugs is to reposition drugs approved for other indications as anti-cancer agents. HIV protease inhibitors (HIV PIs) are useful in treating HIV infection and cause toxicities in humans that are similar to those observed when the kinase Akt, a target for cancer therapy, is inhibited. To test whether HIV PIs inhibited Akt and cancer cell proliferation, we screened 6 HIV PIs and found that three, ritonavir, saquinavir and Nelfinavir, inhibit the growth of over 60 cancer cell lines derived from 9 different tumor types; Nelfinavir is the most potent. Nelfinavir causes caspase-dependent apoptosis and non-apoptotic death, as well as endoplasmic reticulum (ER) stress and autophagy. Nelfinavir blocks growth factor receptor activation and decreases growth factor-induced and endogenous Akt signaling. In vivo, Nelfinavir inhibits tumor growth and upregulates markers of ER stress, autophagy and apoptosis. Nelfinavir is currently being tested in cancer patients in Phase I clinical trials where biomarkers will be assessed. Current studies are focused on measuring autophagy in clinical specimens and identifying combination strategies that will exploit the induction of autophagy and increase the effectiveness of Nelfinavir.
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Nelfinavir a lead hiv protease inhibitor is a broad spectrum anticancer agent that induces endoplasmic reticulum stress autophagy and apoptosis in vitro and in vivo
Clinical Cancer Research, 2007Co-Authors: Joell J Gills, Jaclyn Lopiccolo, Junji Tsurutani, Robert H Shoemaker, Carolyn J M Best, Mones Abuasab, Jennifer P Borojerdi, Noel A Warfel, Erin R Gardner, Matthew DanishAbstract:Purpose: The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents. Experimental Design: HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non–small cell lung carcinoma (NSCLC) xenografts with biomarker assessment. Results: Three of six HIV protease inhibitors, Nelfinavir, ritonavir, and saquinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 μmol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased Nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but Nelfinavir caused the greatest inhibition of endogenous and growth factor–induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis. Conclusions: Nelfinavir is a lead HIV protease inhibitor with pleiotropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, Nelfinavir is a Food and Drug Administration–approved drug that could be repositioned as a cancer therapeutic.
Cynthia Helsabeck - One of the best experts on this subject based on the ideXlab platform.
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a phase i trial of the hiv protease inhibitor Nelfinavir in adults with solid tumors
Oncotarget, 2014Co-Authors: Gideon M. Blumenthal, Joell J Gills, Marc S. Ballas, Wendy B. Bernstein, Takefumi Komiya, Roopa Dechowdhury, Betsy Morrow, Hyejeong Root, Guinevere Chun, Cynthia HelsabeckAbstract:// Gideon M. Blumenthal 1 , Joell J. Gills 3 , Marc S. Ballas 1 , Wendy B. Bernstein 1 , Takefumi Komiya 1 , Roopa Dechowdhury 1 , Betsy Morrow 1 , Hyejeong Root 1 , Guinevere Chun 1 , Cynthia Helsabeck 1 , Seth M. Steinberg 2 , Jaclyn LoPiccolo 1 , Shigeru Kawabata 3 , Erin R. Gardner 1 , William D. Figg 1 , Phillip A. Dennis 3 1 Medical Oncology Branch, National Cancer Institute, Bethesda, MD 2 Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 3 Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA Correspondence to: Phillip A. Dennis, e-mail: pdennis@jhmi.edu Key words: Nelfinavir, phase I clinical trial, AKT, endoplasmic reticulum stress, neuroendocrine Received: June 30, 2014 Accepted: August 28, 2014 Published: September 05, 2014 ABSTRACT Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of Nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of Nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral Nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, Nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
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A phase I trial of the HIV protease inhibitor Nelfinavir in adults with solid tumors
Oncotarget, 2014Co-Authors: Gideon M. Blumenthal, Joell J Gills, Marc S. Ballas, Wendy B. Bernstein, Takefumi Komiya, Roopa Dechowdhury, Betsy Morrow, Hyejeong Root, Guinevere Chun, Cynthia HelsabeckAbstract:Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of Nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of Nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral Nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, Nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
