Hyperglycemia downregulates androgen receptor levels in LNCaP cells.

<p>(<b>A</b>) Relative AR mRNA levels in the presence of different D-glucose concentrations are shown. Human 18S mRNA was amplified as a control. Data points are shown as mean ± SD of triplicates. (<b>B</b>) Analysis of AR protein levels in the presence of different D-glucose concentrations in LNCaP cells by western blot. PPIA has been used as a housekeeping reference protein.</p

Treatment with streptozotocin reduces androgen receptor staining in prostate tumors in PAC120 mouse model.

<p>(<b>A</b>) HE staining of prostate tumor xenografts from control mice, (<b>D</b>) citrate treated mice, (<b>G</b>) STZ-treated before tumor implantation and (<b>J</b>) STZ-treated after tumor implantation. (<b>B</b>) AR staining of prostate tumor xenografts from non-treated mice, (<b>E</b>) citrate treated mice, (<b>H</b>) STZ-treated mice before tumor implantation and (<b>K</b>) STZ-treated mice after tumor implantation. (<b>C</b>) Cytokeratine staining of prostate tumor xenografts from control mice, (<b>F</b>) citrate treated mice, (<b>I</b>) STZ-treated mice before tumor implantation and (<b>L</b>) STZ-treated mice after tumor implantation.</p

Treatment with streptozotocin reduces prostate tumor growth in PAC120 mouse model.

<p>(<b>A</b>) Pictures of tumors developed in vehicle treated mice (n = 5) (i), STZ treated after or before tumor implantation (n = 7 for both) with reduced (ii) or no tumor growth (iii). (<b>B</b>) Comparison of tumor volume for non-treated (n = 5) and citrate treated (n = 5) mice. (<b>C</b>) Tumor volume of STZ-treated animals after tumor implantation compared with tumor volume of citrate treated mice. (<b>D</b>) Tumor volume of STZ-treated animals before tumor implantation compared with tumor volume of citrate treated mice. Data are mean ± SD. *P<0.05 and **P<0.01 compared with the control.</p

Analysis of the androgen receptor and p65 levels in tumor xenografts of control and STZ treated mice.

<p>(<b>A</b>) Relative AR mRNA levels for citrate and STZ-treated mice. Human 18 S mRNA was amplified as a control. Data points are shown as mean ± SD of triplicates. (<b>B</b>) Analysis of AR (left panel) and phospho-p-65 (right panel) protein levels from citrate and STZ-treated mice measured by Western blotting using PPIA as a housekeeping reference protein.</p

Synergic effects of hyperglycemia and TNFα on the androgen receptor downregulation in LNCaP cells.

<p>(<b>A</b>) Relative AR mRNA levels in LNCaP treated with an increasing concentration of D-glucose with or without TNFα. Human 18 S mRNA was amplified as a control. Data points are shown as mean ± SD of triplicates. *P<0.05 and **P<0.01 compared with 5 mM of D-glucose. (<b>B</b>) Analysis of AR protein levels in LNCaP cells treated as in <b>A</b> measured by Western blotting using PPIA as a housekeeping reference protein.</p

Hyperglycemia reduces androgen receptor levels via NF-κB activation in LNCaP cells.

<p>(<b>A</b>) Relative AR mRNA levels in LNCaP treated with 5 mM or 30 mM glucose. Human 18 S mRNA was amplified as a control. Data points are shown as mean ± SD of triplicates. *P<0.05 and **P<0.01 compared with 5 mM glucose. (<b>B</b>) Analysis of AR and phospho-p-65 protein levels in LNCaP cells treated as in <b>A</b> measured by Western blotting using PPIA as a housekeeping reference protein. (<b>C</b>) Relative AR mRNA levels in LNCaP treated with 5 mM or 30 mM glucose in the absence or presence of QNZ (25 nM). Human 18 S mRNA was amplified as a control. Data points are shown as mean ± SD of triplicates. *P<0.05 and **P<0.01 compared with 5 mM glucose. (<b>D</b>) Analysis of AR protein levels in LNCaP cells treated as in <b>C</b> measured by Western blotting using PPIA as a housekeeping reference protein.</p

Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide-0

<p><b>Copyright information:</b></p><p>Taken from "Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide"</p><p>http://www.biomedcentral.com/1471-2210/7/13</p><p>BMC Pharmacology 2007;7():13-13.</p><p>Published online 27 Oct 2007</p><p>PMCID:PMC2180168.</p><p></p> alone (E) at a dosage of 12 mg/kg in one daily intraperitoneal injection on days 1 to 3 (▲), etoposide (VP16) and STI571 (E + S) administered by one daily intraperitoneal injection at a dose of 70 mg/kg on days 1 to 3 (■), etoposide (VP16) and fluconazole (E + F) at a dosage of 40 mg/kg in one daily intraperitoneal injection on days 1 to 3 (○), or etoposide (VP16) with STI571 and fluconazole (E + S + F)(◇). All other groups included STI571 alone (S)(□), fluconazole alone (F)(△), and STI571 + fluconazole (S + F)(◆) and 0.9% NaCl (●). (B) Mice bearing LY-3 tumors were treated by one (□) daily intraperitoneal injection of STI571 (S) at a dose of 70 mg/kg from day 1 until sacrifice of the animals. (D) Xenografted LY-3 tumors were treated by gemcitabine at a dosage of 60 mg/kg by one weekly intraperitoneal injection, with (G + S)(■) or without (G)(▲) STI571 administered by one daily intraperitoneal injection at a dose of 70 mg/kg from day 1 until sacrifice of the animals. Mice treated by STI571 alone (S) are indicated by (□). All control groups received injections of 0.9% NaCl (Control)(●). Tumor growth was evaluated by measuring the relative tumor volume (RTV), as described in "Materials and Methods". A Mann-Whitney test was used to assess the effects of treatments on xenografted tumor growth

Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide-3

<p><b>Copyright information:</b></p><p>Taken from "Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide"</p><p>http://www.biomedcentral.com/1471-2210/7/13</p><p>BMC Pharmacology 2007;7():13-13.</p><p>Published online 27 Oct 2007</p><p>PMCID:PMC2180168.</p><p></p> alone (E) at a dosage of 12 mg/kg in one daily intraperitoneal injection on days 1 to 3 (▲), etoposide (VP16) and STI571 (E + S) administered by one daily intraperitoneal injection at a dose of 70 mg/kg on days 1 to 3 (■), etoposide (VP16) and fluconazole (E + F) at a dosage of 40 mg/kg in one daily intraperitoneal injection on days 1 to 3 (○), or etoposide (VP16) with STI571 and fluconazole (E + S + F)(◇). All other groups included STI571 alone (S)(□), fluconazole alone (F)(△), and STI571 + fluconazole (S + F)(◆) and 0.9% NaCl (●). (B) Mice bearing LY-3 tumors were treated by one (□) daily intraperitoneal injection of STI571 (S) at a dose of 70 mg/kg from day 1 until sacrifice of the animals. (D) Xenografted LY-3 tumors were treated by gemcitabine at a dosage of 60 mg/kg by one weekly intraperitoneal injection, with (G + S)(■) or without (G)(▲) STI571 administered by one daily intraperitoneal injection at a dose of 70 mg/kg from day 1 until sacrifice of the animals. Mice treated by STI571 alone (S) are indicated by (□). All control groups received injections of 0.9% NaCl (Control)(●). Tumor growth was evaluated by measuring the relative tumor volume (RTV), as described in "Materials and Methods". A Mann-Whitney test was used to assess the effects of treatments on xenografted tumor growth

Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide-1

<p><b>Copyright information:</b></p><p>Taken from "Impact of imatinib on the pharmacokinetics and efficacy of etoposide and/or ifosfamide"</p><p>http://www.biomedcentral.com/1471-2210/7/13</p><p>BMC Pharmacology 2007;7():13-13.</p><p>Published online 27 Oct 2007</p><p>PMCID:PMC2180168.</p><p></p>ase time (0) and 3 hours after administration of etoposide alone or etoposide plus fluconazole or etoposide plus imatinib or etoposide with imatinib and fluconazole. . After administration of etoposide (VP16) with STI571, concentrations of VP16 peaked at 30.9 ± 2.1 ng/mL, followed by a bi-exponential decline.

Risk of Hormone Escape in a Human Prostate Cancer Model Depends on Therapy Modalities and Can Be Reduced by Tyrosine Kinase Inhibitors

<div><p>Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape -frequency and delay- are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR_intermittent: 14.5, RR_{complete blockade}: 6.5 and 1.35). All recurrent tumors displayed <em>new</em> quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.</p> </div