Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model

Insulin-like growth factor 1 (IGF-1) plays a pleiotropic role in multiple myeloma (MM), that is, in survival, proliferation, chemotaxis, and angiogenesis. Strategies targeting the IGF-1 receptor (IGF-1R) may therefore be important to develop efficient anti-MM agents. In this work we investigated the effect of an IGF-1R tyrosine kinase (IGF-1RTK) inhibitor (picropodophyllin or PPP) in the 5T33MM mouse model. In vitro data showed that PPP reduced IGF-1R autophosphorylation and downstream ERK activation, leading to inhibition of IGF-1-stimulated proliferation and vascular endothelial growth factor (VEGF) secretion of MM cells. In an in vivo study, PPP reduced the bone marrow tumor burden and serum paraprotein in 5T33MM mice by 77% and 90%, respectively, compared to vehicle-treated animals. Angiogenesis was assessed by quantifying the microvessel density on CD31-stained paraffin sections and this was reduced by 60% in the PPP-treated group. In a separate survival experiment, Kaplan-Meier analysis demonstrated a significant increase in survival in PPP-treated 5T33MM animals compared to the vehicle controls (28 versus 18 days). These data suggest that the IGF-1RTK inhibitor PPP possesses a marked antitumor activity and strongly points to the possibility of using IGF-1R inhibitors in the treatment of MM.     

Vas deferens urethral support improves early post-prostatectomy urine continence

Urine continence is often impaired after radical prostatectomy. Few randomized studies prove the efficacy of novel surgical approaches. Vas deferens urethral support (VDUS) during robot-assisted laparoscopic prostatectomy (RALP) was studied for improvement of early postoperative urine continence in a single-centre prospective double-blind randomized study with a power of 90% to detect a 30% decrease in early incontinence. 112 men were randomized, and 108 could be analyzed (VDUS n?=?54, noVDUS n?=?54). VDUS improved early continence by 40% at 1?month (59% vs. 35%, P?=?0.02); 6 months postoperatively this was 72% vs. 62%, P?=?0.41. A 24-h pad test at 1?day, 3?days, and 1?week showed decreased amounts of urine loss in the VDUS group. The ICIQ-SF score was significantly lower for the VDUS group within the first month after surgery. VDUS had no impact upon quality of life questionnaire analyses for overall and lower urinary tract symptom-related quality of life but showed a significant improvement in the social domain of the EORTC-QLQ-C30 questionnaire. VDUS moderately improved early urine continence within 1?month after RALP.