In vitro activity of bortezomib in cultures of patient tumour cells--potential utility in haematological malignancies.

Bortezomib represents a new class of anti-cancer drugs, the proteasome inhibitors. We evaluated the in vitro activity of bortezomib with regard to tumour-type specificity and possible mechanisms of drug resistance in 115 samples of tumour cells from patients and in a cell-line panel, using the short-term fluorometric microculture cytotoxicity assay. Bortezomib generally showed dose-response curves with a steep slope. In patient cells, bortezomib was more active in haematological than in solid tumour samples. Myeloma and chronic myeloid leukaemia were the most sensitive tumour types although with great variability in drug response between the individual samples. Colorectal and kidney cancer samples were the least sensitive. In the cell-line panel, only small differences in response were seen between the different cell lines, and the proteasome inhibitors, lactacystin and MG 262, showed an activity pattern similar to that of bortezomib. The cell-line data suggest that resistance to bortezomib was not mediated by MRP-, PgP, GSH-; tubulin and topo II-associated MDR. Combination experiments indicated synergy between bortezomib and arsenic trioxide or irinotecan. The data support the current use of bortezomib but also points to its potential utility in other tumour types and in combination with cytotoxic drugs.

Monoclonal Antibodies Recognizing Normal and Neoplastic Human Adrenal Cortex.

Four monoclonal antibodies (MAb) were generated by immunization of mice with dispersed cells from normal human adrenal gland (Na) and adrenocortical adenoma causing cortisol excess (Ac). Immunohistochemically reacted cryosections revealed differential labeling of the normal cortical parenchyma, and immunofluorescence on dispersed cells displayed that Ac5 alone labeled the cell surface. Immunoprecipitation demonstrated that the antibodies recognized apparently different structures of 51-88 kDa. Immunohistochemical examination of several normal human tissues substantiated restricted reactivity, especially for the Na2 and Na7 antibodies, and that the adrenal medulla was not stained by any of the antibodies. The antibodies recognized the vast majority of the parenchymal cells of cortical adenomas (n = 21). Each antibody also reacted with all adrenocortical carcinomas (n = 17), and the staining generally was most intense and extensive with Na7. Analysis of other pathological human tissues revealed highly restricted reactivity for the Na2 antibody. Na2 and Na5 failed to stain 17 renal cell carcinomas. None of the antibodies recognized pheochromocytomas. These antibodies may lead to improved histological recognition and characterization of human adrenal lesions.