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.

Effect of DPT-C9h on caspase-9 activation, mitochondrial membrane depolarization, cytochrome <i>c</i> release and cell cycle.

<p>A) HBCx-3 cells were cultured for 3 or 6 h with medium (control), 100 µM of DPT-C9h or 10 µM of the caspase inhibitor Z-VAD (pre incubation of 1h) and 100 µM of DPT-C9h. Caspase-9 activity was estimated using a luminogenic substrate. Results are represented relative to control non-treated cells as arbitrary units. P values are shown. B) HBCx-3 cells were cultured for 24 h with medium (control), DPT-Sh1 (100 µM), DPT-C9h (100 µM) or Z-VAD (10 µM, pre incubation of 1h) and DPT-C9h (100 µM). Apoptosis was estimated by Annexin-V-FITC binding. C) HBCx-3 cells were treated for different periods of time with DPT-C9h (100 µM) and then incubated for 30 min at 37°C protected from the light with the fluorescent probe JC-10. Green and red fluorescence were measured. Data are represented relative to the control non-treated cells. P values are shown. D) HBCx-12A and HBCx-3 cell lines were treated for 24 h with 100 µM of DPT-C9 h. Mitochondrial fraction was separated from whole cell lysates and immunoblotted for cytochrome <i>c</i>. The WB was also hybridized with the mitochondrial marker Tim23 as internal control of protein loading. E) HBCx-3 cells were non-treated (control) or treated with 10 or 25 µM of DPT-C9h for 24 or 48 h and the cell cycle was analyzed by FACS.</p

Apoptotic effect of DPT-C9h peptide on primary and tumour cells.

<p><b>A</b>) Peripheral blood mononuclear cells (PBMC) from healthy donors or CLL patients were cultured in the presence of DPT-C9h (150 µM) for 3 h, then washed, transferred to complete medium and apoptosis was estimated 6h later. Selection of B cells was done by anti-CD19 antibody before Annexin V-FITC staining. Non-treated cells were used as control. <b>B</b>) Cells isolated from bone marrow of CLL patients and healthy donors were treated as in A and analyzed for apoptosis. P values are shown.</p

DPT-C9h induces apoptosis in human cell lines.

<p><b>A</b>) Daudi, Jurkat, and HeLa cell lines were cultured in the presence of DPT-C9h, DPT-Sh1, C9h, or C9 peptides for 20 h at 100 µM and apoptosis was estimated by Annexin-V staining. <b>B</b>) Mouse lung cancer cell lines LKR10 and LKR13 were cultured in the presence of DPT-C9h, DPT-C9, or DPT-Sh1 at 100 µM. After 24 h of incubation, apoptosis was estimated by Annexin staining. The basal level of apoptosis of control non-treated cells is shown. P values are also shown (*<0.05; **<0.001; ***<0.0001). <b>C</b>) Breast, uveal melanoma and lung cancer cell lines isolated from primary human xenografs were cultured in the presence or absence of DPT-C9h peptide (100 µM) for 24h and apoptosis was estimated by Annexin V-FITC. Basal level of apoptosis without peptide addition is shown (grey colour) p values are shown. <b>D</b>). Breast cancer cell lines derived from the primary human xenografts, were incubated with C9h in culture medium at 150 µM and apoptosis induction was estimated at different times. <b>E</b>) Breast cancer cell lines isolated from primary human xenografts BCx-3 and Bcx-12 were cultured in the presence or absence (control) of the peptide DPT-C9h for 24 h and apoptosis was estimated.</p

<i>In vivo</i> antibody responses and toxicity induced by DPT-C9h.

<p><b>A</b><b> </b>) Serum antibodies taken from nude mice treated for different periods of time were detected by ELISA at two different concentrations of DPT-C9h peptide (10 and 50 µM). <b>B</b>) Serum antibodies from wild type mice treated for different periods for time were tested by ELISA against DPT-C9h and DPT-Sh1 (50 µM). <b>C</b>) DPT-C9h was intraperitoneally administered in mice bearing tumors HBCx-12A at 1, 5, or 25 mg/kg once daily for 5 weeks; the median weight of mice for each experimental group is represented at different times. A total of 10 mice were included per group. Similarly, DPT-C9h was intraperitoneally administered in mice bearing tumours HBCx-8 at 10 mg/kg twice daily for 4 weeks. DPT-C9 was IP administrated at mice model PyMT model at dose of 5 mg/kg. The median weight of mice for each experimental group is represented at different times. Ten mice were included per group.</p

Immunohistochemical analyses under S44563 administration.

<p>Immunohistochemical analyses of the MM66 UM xenograft after S44563, fotemustine, or S44563+fotemustine.</p

Correlation between <i>HLA-</i> gene expression and the expression of the genes encoding the HLA transcriptional regulators and peptide-loading machinery.

<p>Correlation between <i>HLA-</i> gene expression and the expression of the genes encoding the HLA transcriptional regulators and peptide-loading machinery.</p

Schematic illustration of tumor characteristics and infiltrate.

<p>UM with monosomy 3 attract an infiltrate, producing different cytokines, including Interferon-gamma. The tumor cell (UM cell) responds by increasing HLA class I and II levels, as well as rendering the infiltrating immune cells ineffective (immune suppression) and creating a tumor-favorable environment, with amongst others, stimulation of angiogenesis.</p