Figure 4
Figure 4. Oral administration of the IGF1R inhibitor linsitinib decreases the amount of CD5/CD19+ cells of Eµ-Tcl1 transgenic mice in vivo and reduces tumor engraftment, spleen, and BM infiltration in NOD/SCID common γ chain–deficient (NSG) mice. (A) B cells (CD5+/CD19+) purified from the spleens of Eµ-Tcl1 transgenic mice were treated with 1 to 50 µM linsitinib for 24 hours, and cell survival was determined by flow cytometry (mean ± SEM, n = 10). (B) Female and male Eµ-Tcl1 transgenic mice were randomized into 2 groups of 5 animals each and treated with 25 mg/kg linsitinib by oral gavage once per day for 8 days. The amount of CD5+/CD19+ cells was assessed at days 0, 4, and 8 by collecting tail vein blood and staining for CD5 and CD19. Results are represented relative to vehicle-treated control mice (n = 5 per group). (C) NSG mice were injected with 1 × 108 B-CLL patient-derived PBMCs intravenously and 1 × 108 PBMCs intraperitoneally. Seven days thereafter, mice were randomized into 2 groups of 6 animals each, treated with ClinOleic 20% (Baxter) (10 mL/kg per day orally on days 7-19) or linsitinib (25 mg/kg per day orally on days 7-19; Selleckchem), and tumor size and intensity was measured at different time points. After antibody injection, mice were anesthetized by isoflurane inhalation and images were taken using a Kodak in vivo imaging system (Kodak Image Station in vivo FX). In addition, animals were radiographed and the 2 pictures merged for optimal localization of the fluorescent region. Two representative images for the control and treatment groups are shown (n = 6 per group). (D-E) NSG mice were injected with 1 × 108 B-CLL patient-derived PBMCs intravenously and 1 × 108 PBMCs intraperitoneally. Seven days thereafter, mice were randomized into 2 groups of 6 animals each and treated with ClinOleic 20% (Baxter) (10 mL/kg per day orally on days 7-19) or linsitinib (25 mg/kg per day orally on days 7-19; Selleckchem), and cell engraftment was assessed in the spleen (D) and BM (E). Tumor cell growth repression was calculated as the reduction of human tumor cells compared with untreated mice (n = 6 per group).

Oral administration of the IGF1R inhibitor linsitinib decreases the amount of CD5/CD19+ cells of Eµ-Tcl1 transgenic mice in vivo and reduces tumor engraftment, spleen, and BM infiltration in NOD/SCID common γ chain–deficient (NSG) mice. (A) B cells (CD5+/CD19+) purified from the spleens of Eµ-Tcl1 transgenic mice were treated with 1 to 50 µM linsitinib for 24 hours, and cell survival was determined by flow cytometry (mean ± SEM, n = 10). (B) Female and male Eµ-Tcl1 transgenic mice were randomized into 2 groups of 5 animals each and treated with 25 mg/kg linsitinib by oral gavage once per day for 8 days. The amount of CD5+/CD19+ cells was assessed at days 0, 4, and 8 by collecting tail vein blood and staining for CD5 and CD19. Results are represented relative to vehicle-treated control mice (n = 5 per group). (C) NSG mice were injected with 1 × 108 B-CLL patient-derived PBMCs intravenously and 1 × 108 PBMCs intraperitoneally. Seven days thereafter, mice were randomized into 2 groups of 6 animals each, treated with ClinOleic 20% (Baxter) (10 mL/kg per day orally on days 7-19) or linsitinib (25 mg/kg per day orally on days 7-19; Selleckchem), and tumor size and intensity was measured at different time points. After antibody injection, mice were anesthetized by isoflurane inhalation and images were taken using a Kodak in vivo imaging system (Kodak Image Station in vivo FX). In addition, animals were radiographed and the 2 pictures merged for optimal localization of the fluorescent region. Two representative images for the control and treatment groups are shown (n = 6 per group). (D-E) NSG mice were injected with 1 × 108 B-CLL patient-derived PBMCs intravenously and 1 × 108 PBMCs intraperitoneally. Seven days thereafter, mice were randomized into 2 groups of 6 animals each and treated with ClinOleic 20% (Baxter) (10 mL/kg per day orally on days 7-19) or linsitinib (25 mg/kg per day orally on days 7-19; Selleckchem), and cell engraftment was assessed in the spleen (D) and BM (E). Tumor cell growth repression was calculated as the reduction of human tumor cells compared with untreated mice (n = 6 per group).

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