Andreas Stadlmayr

Chronic arthropathy occurs in approximately two thirds of patients with hereditary haemochromatosis (HH). The aim was to study inflammatory and structural lesions in patients with HH with (HH-A) and without arthropathy (HH-WA) using ultrasonography. This was a cross-sectional study of 26 patients with HH-A, 24 with HH-WA and 37 with hand osteoarthritis (HOA). Clinical examination was performed in 68 joints, and we retrieved data on hand function, pain and global disease activity (all using a visual analogue scale (VAS)), morning stiffness and ferritin levels. Standard x-ray and ultrasound were conducted in 36 joints (hands, hips, knees and ankles), and we graded grey scale synovitis (GSS), power Doppler ultrasound (PD), osteophytes, erosions, tenosynovitis and cartilage damage semi-quantitatively in accordance with prior publications. Ultrasound revealed a high proportion of inflammatory changes in HH-A; GSS was found in 96.2% and PD signals in 80.8% of patients (median GSS score 9, PD score 2.5). The frequency of these findings was similar in HOA. Inflammation was also common in HH-WA, yielding GSS in 83.3% and PD signals in 50.0% of patients. Cartilage damage was most prominent in HH-A as compared to HH-WA and HOA (median scores 11.0, 2.5 and 2.0, respectively). The prevalence and extent of erosions and osteophytes were similar in all groups. None of the ultrasound scores was associated with pain or function; GSS, PD, osteophyte and cartilage scores correlated with x-ray-verified structural damage. A high prevalence of ultrasound-verified inflammation and cartilage damage was found in HH-A, and to a lesser extent in HH-WA. These findings were associated with x-ray-verified damage but not with clinical scores of pain and function.

Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 μM) combined with 5-FU (1.25 μM), irinotecan (1.25 μM) or cisplatin (1.25 μM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G1 fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40–55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts to 56–85%. Our observations indicate that JMR-132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase.

We investigated the efficacy of a powerful antagonist of bombesin/gastrin-releasing peptide (BN/GRP) RC-3940-II administered as a single agent or in combination with cytotoxic agents on the growth of HT-29, HCT-116 and HCT-15 human colon cancer in vitro and in vivo. GRP-receptor mRNA and protein were found in all three cell lines tested. Exposure of HT-29 cells to 10 μM RC-3940-II led to an increase in the number of cells blocked in S phase and G2/M and cells with lower G0/G1 DNA content. Similar changes on the cell cycle traverse of HT-29 cells could also be seen at lower concentrations of RC-3940-II (1 μM) after pretreatment with 100 nM GRP (14–27), indicating a dose-dependent mechanism of action based on the blockage of BN/GRP induced proliferation of tumor cells at lower concentrations. Daily in vivo treatment with BN/GRP antagonist RC-3940-II decreased the volume of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice by 25 to 67% (p < 0.005). Combined treatment with RC-3940-II and chemotherapeutic agents 5-FU and irinotecan resulted in a synergistic tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts by 43% to 78%. In HT-29 and HCT-116 xenografts the inhibition for the combinations of RC-3940-II and irinotecan vs. single substances (p < 0.05) was significantly greater. These findings support the use of RC-3940-II as an anticancer agent and may help to design clinical trials using RC-3940-II in combinations with cytotoxic agents.

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