Citations

Hepatitis C-associated osteosclerosis (HCAO) is a rare syndrome of adult-onset osteosclerosis. An understanding of the factor(s) leading to the stimulation of bone formation in these patients may provide novel anabolic approaches for the treatment of osteoporosis. We have demonstrated that HCAO patients have a specific increase in circulating big IGF-II (IGF-IIE) and IGF-binding protein-2 (IGFBP-2) levels, and that IGF-IIE and IGFBP-2 circulate together in a bioavailable, 50-kDa complex. Patients with nonislet cell tumor hypoglycemia (NICTH) also have increased circulating IGF-IIE and IGFBP-2 levels. However, HCAO patients do not exhibit hypoglycemia, nor do NICTH patients exhibit obvious osteosclerosis. Thus, to better understand the reason(s) for the differing clinical manifestations of the IGF-IIE excess in the two syndromes, we characterized IGF-IIE in HCAO and NICTH sera using recently developed antibodies (Ab) recognizing either the full-length IGF-IIE 89-amino acid C-terminal extension peptide (IIE138–156 Ab) or specific cleavage forms of IGF-IIE (IIE78–88 Ab and IIE89–101 Ab). The predominant IGF-IIE form in HCAO serum migrated on SDS-PAGE as a single band at approximately 18 kDa that reacted with the IIE89–101 Ab. On the other hand, the predominant form in NICTH serum migrated as a doublet of 14 and 16 kDa that reacted with the IIE78–88 Ab. There results are consistent with differential processing of the IGF-IIE precursor at predicted cleavage sites producing IGF-IIE1–104 and IGF-IIE1–88 in HCAO and NICTH, respectively. As these two forms may have differing biological activities and/or targeting properties, our findings may explain at least in part the different manifestations of IGF-IIE overproduction in the two syndromes.

To evaluate the potential application of somatostatin (SST) analogs as an adjuvant treatment for prostate cancer, we characterized the binding sites for SST octapeptide analogs on prostate cancers in patients treated with radical prostatectomy. The affinity and density of binding sites for SST analog RC-160 on 80 surgical specimens of prostate cancers were determined by ligand competition assays. The expression of messenger ribonucleic acid (mRNA) for SST receptor subtype 1 (SSTR1), subtype 2 (SSTR2), and subtype 5 (SSTR5) was also investigated in 22 samples by RT-PCR. Fifty-two of 80 specimens (65%), showed a single class of specific binding sites for RC-160 with a mean dissociation constant (Kd) of 9.44 nmol/L and a mean maximal binding capacity of 754.8 fmol/mg membrane protein. The mRNA for SSTR1 was detected in 86% of samples, whereas the incidences of mRNA for SSTR2 and SSTR5 were 14% and 64%, respectively. The expression of SSTR2 and/or SSTR5 was 100%, consistent with the presence of RC-160 binding. In patients at high risk of cancer recurrence (stage pT3 and/or Gleason score of 8–10), the incidence of RC-160 binding (65.7%) was similar to that observed in the low risk group (64.3%). The demonstration of the high incidence of octapeptide-preferring SSTRs in organ-confined and locally advanced prostate cancers supports the merit of further investigations of the application of SST analogs and their radionuclide and cytotoxic derivatives for adjuvant treatment of patients at high risk of cancer recurrence after radical prostatectomy. Such approaches could be also considered for patients with advanced prostate cancer at the time of relapse.