The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS-341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21(Cip1-Waf-1), a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS-341 significantly inhibited tumor growth. Both cellular apoptosis and p21(Cip1-Waf-1) protein levels were increased in PS-341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS-341 was combined with the tumoricidal agent CPT-11. Combined CPT-11/PS-341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF-kappaB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy.

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Iodothyronines were measured by RIA in concentrated human cerebrospinal fluid (CSF). In measurements performed in one laboratory at a 4-fold concentration of CSF, rT3 was detected in all 30 patients in whom the measurement was attempted and averaged 15.1 +/- 2.8 ng/dl (mean +/- SE). IN an independent laboratory, rT3 measurements at this 4-fold concentration were performed on 11 different samples and averaged 9.3 +/- 0.9 ng/dl, while at a 40-fold CSF concentration, rT3 averaged 13.1 +/- 0.72 ng/dl. CSF T3 values were detected in only 4 of 30 patients as a 4-fold concentration and averaged 8.2 +/- 3.1 ng/dl, while in pooled CSF at a 40-fold concentration, 4 of 4 samples were detectable and averaged 2.6 +/- 0.4 ng/dl. Levels of T4 could only be detected in CSF concentrated 40-fold and averaged 0.22 +/- 0.04 microgram/dl. Values for the percent dialyzable thyronines were 0.44 +/- 0.03% for T4, 4.39 +/- 0.29% for T3, and 0.91 +/- 0.04% for rT3. TSH was detected in CSF concentrated 4-fold, averaging 0.43 +/- 0.05 microunits/ml; in an independent assay with CSF concentrated 40-fold, TSH averaged 0.06 +/- 0.02 microunits/ml. Thyroid binding globulin was undetectable (less than 0.1 mg/dl). We have confirmed the presence of thyroid hormones (T4 and T3) in human CSF and have shown that rT3 is present as well. The role these hormones play in the development, function, and nourishment of the central nervous system and the role the CSF plays in the transport of these hormones into the central nervous system remains to be determined.