Lethality caused by extended administration of bortezomib is attributable to gut toxicity. Lethally irradiated (1000 cGy) B6 mice underwent transplantation with TCD B10.BR BM alone or with spleen cells adjusted to yield a dose of 2 × 106 B10.BR T cells. Mice that received transplanted B10.BR T cells were treated with PBS or bortezomib (1 mg/kg twice weekly beginning on day 3). Eight days after transplantation, prior to demise, mice from each of the 3 cohorts were killed, and samples of colon tissue were analyzed for evidence of pathologic damage. Hematoxylin and eosin stains of colon tissue obtained from these mice are depicted (original magnification, 200 ×). (A) Colon tissue from a representative mouse that underwent transplantation with TCD BM only showing normal-appearing colon tissue with intact crypts lined by mucin-filled enterocytes. (B) PBS-treated mouse undergoing GVHD showing increased mitotic activity at the base of crypts associated with a few crypt abscesses (solid arrows). (C) Bortezomib-treated animal demonstrating extensive crypt destruction with sloughing of the colonic mucosa (dashed arrows), goblet cell depletion, and numerous crypt abscesses (solid arrows).
