The experimental compound SU5416 went as far as Phase III clinical trials as an anticancer agent, putatively because of its activity as a VEGFR-2 inhibitor, but showed poor results. Here, we show that SU5416 is also an aryl hydrocarbon receptor (AHR) agonist with unique properties. Like TCDD, SU5416 favors induction of indoleamine 2,3 dioxygenase (IDO) in immunologically relevant populations such as dendritic cells in an AHR-dependent manner, leading to generation of regulatory T-cells in vitro. These characteristics lead us to suggest that SU5416 may be an ideal clinical agent for treatment of autoimmune diseases and prevention of transplant rejection, two areas where regulatory ligands of the AHR have shown promise. At the same time, AHR agonism might represent a poor characteristic for an anticancer drug, as regulatory T-cells can inhibit clearance of cancer cells, and activation of the AHR can lead to upregulation of xenobiotic metabolizing enzymes that might influence the half-lives of co-administered chemotherapeutic agents. Not only does SU5416 activate the human AHR with a potency approaching 2,3,7,8-tetrachlorodibenzo-p-dioxin, but it also activates polymorphic murine receptor isoforms (encoded by the Ahrd and Ahrb1 alleles) with similar potency, a finding that has rarely been described and may have implications in identifying true endogenous ligands of this receptor.

Background Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the gold standard surgical treatment for chronic ulcerative colitis. More recently, this procedure is being performed laparoscopically assisted. Postoperatively, small bowel obstruction (SBO) is one of the more common associated complications. However, it is unknown whether the addition of a laparoscopic approach has changed this risk. This study aims to assess and compare the incidence of SBOs after both open and laparoscopic restorative proctocolectomy. Methods All subjects who underwent restorative proctocolectomy from 1998–2008 were identified from a prospective Colorectal Surgery Database. Medical records were reviewed for all cases of SBO, confirmed by a combination of clinical symptoms and radiologic evidence. Comparisons were made between laparoscopic and open approaches. The incidence of SBO was also subdivided into pre-ileostomy takedown, early post-ileostomy takedown (30 d post), and late post-ileostomy takedown (30 d to 1 y post). Several potential risk factors were also evaluated. Statistical analysis was performed utilizing Fisher’s exact (for incidence) or t-tests (for means). Significance was defined as P < 0.05 Results A total of 290 open cases and 100 laparoscopic cases were identified during this time period. The overall incidence of SBO at 1 y post-ileostomy takedown was 14% (n = 42) in the open group and 16% (n = 16) laparoscopic (P = NS). In the pre-ileostomy takedown period the incidence of SBO was 7% (n = 21) open and 13% (n = 13) laparoscopic (P = NS). While in the post-takedown period, the early incidence was 4% (n = 12) open and 1% (n = 1) laparoscopic and late incidence was 3% (n = 9) open and 2% (n = 2) laparoscopic (P = NS). Factors associated with an increased risk of SBO include coronary artery disease, prior appendectomy and W and J pouch configurations. Conclusions The burden of postoperative small bowel obstruction after restorative proctocolectomy is not changed with a laparoscopic approach. Most cases occur in the early postoperative period, especially prior to ileostomy reversal.

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