Harald Hofer

25-Hydroxyvitamin D3-1α-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis

Human colorectal cancer cells not only express the nuclear vitamin D receptor (VDR) but are also endowed with 25-hydroxy-vitamin D(3)-1alpha-hydroxylase activity and therefore are able to produce the specific ligand for the VDR, the hormonally active steroid 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)). In the present study we show by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) as well as by Western blotting and immunohistochemical methods, that in human large intestinal carcinomas expression of the genes encoding the 25-(OH)D(3)-1alpha-hydroxylase as well as the VDR increases in parallel with ongoing dedifferentiation in the early phase of cancerogenesis, whereas in poorly differentiated late stage carcinomas only low levels of the respective mRNAs can be detected. This indicates that, through up-regulation of this intrinsic 1alpha,25(OH)(2)D(3)/VDR system which mediates the anti-mitotic effects of the steroid hormone, colorectal cancer cells are apparently able to increase their potential for an autocrine counter-regulatory response to neoplastic cell growth, particularly in the early stages of malignancy.

Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study

Summary Only 30% of patients with chronic hepatitis C virus genotype 1 (HCV-1) infection achieve a sustained virological response to interferon and ribavirin combination therapy. We prospectively assessed decline in viral load 24 h after one dose of interferon alfa as a predictor of non-response to 6 months of treatment with interferon and ribavirin. Interferon sensitivity was measured before initiation of combination therapy. We measured viral load in 29 consecutive patients, who had not previously been treated with interferon and who were chronically infected with HCV-1 within 24 h after one dose of 5 MU or 10 MU interferon alfa-2b, and 14 days of daily 5 MU interferon alfa-2b. A 24 h viral load decline by less than 70% of baseline after 5 MU interferon was the best pretreatment measure to identify non-responders (specificity 100%, n=10, 95% CI 74–100], sensitivity 83% [15/18], 59–96]).

Growth regulation of human colon cancer cells by epidermal growth factor and 1,25-dihydroxyvitamin D3 is mediated by mutual modulation of receptor expression

The human colon adenocarcinoma-derived cell line Caco-2 was used as a model system to study the interaction of epidermal growth factors (EGF) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in control of colorectal cancer cell growth. The mitogenic stimulus of EGF was rapidly transduced via apical and basal membrane receptors alike into elevation of c-myc expression, causing a shift of Caco-2 cells from the G0/G1 into the S phase of the cell cycle. The stimulatory effect of EGF on cell division was effectively counteracted by 1,25(OH)2D3: the presence of the steroid hormone prevents the negative effect of EGF on vitamin D receptor abundance and concurrently minimises ligand-occupied EGF receptor numbers on both sides of Caco-2 cell monolayers. Our data suggest that EGF and 1,25-(OH)2D3 actions on mutual receptor levels represent a specific feature of the potent antimitogenic effect of the steroid hormone on colon cancer cells.

Early viral kinetics on treatment with pegylated interferon-alpha-2a in chronic hepatitis C virus genotype 1 infection.

summary. Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG‐IFN‐α‐2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN‐α‐2a (days 0 and 1), and before and during weekly 180 μg PEG‐IFN‐α‐2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty‐eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV‐RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN‐α‐2a was greater in virological responders (1.05 log [0.25–1.67]) than in nonresponders (NR) (0.34 [0.14–0.65]; P=0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG‐IFN‐α‐2a. All patients with an initial decline >u20031.4 log became sustained responders. Five of 12 patients with a log change <u20030.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG‐IFN‐α‐2a is different to that on standard IFN. In spite of a lower initial response PEG‐IFN‐α‐2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.

Impact of high‐dose interferon induction and ribavirin therapy in patients with chronic hepatitis C relapsing after or not responding to interferon monotherapy

Background/aims: Initial high‐dose interferon‐α induction therapy in combination with ribavirin improves sustained response rates in treatment‐naïve patients. This prospective, randomized, controlled study tested whether non‐responders or relapsers to interferon monotherapy also benefit from induction therapy.

Retreatment of patients with chronic hepatitis C not responding to interferon/ribavirin combination therapy with daily interferon plus ribavirin plus amantadine

SummaryThere is currently no accepted therapeutic regimen for patients with chronic hepatitis C who failed to respond to standard combination treatment with interferon-α plus ribavirin. We investigated triple combination treatment with induction dosing of interferon-α plus ribavirin plus amantadine in these difficult-to-treat patients. Nonresponders (n=67), breakthroughs (n=16) and relapsers (n=19) to previous interferon/ribavirin combination treatment of at least 6 months were included. For the first 16 weeks, patients received interferon-α2a 6MU daily, ribavirin 800–1200 mg/d, and amantadine 200 mg/d. In cases of undetectable HCV RNA at week 12, treatment was continued with interferon-α2a 6MU every other day and the same doses of ribavirin and amantadine until week 48. In cases of HCV RNA positivity at week 12, treatment was stopped. A total of 102 patients were enrolled (80%: genotype 1, 19%: cirrhosis). HCV RNA was negative in 35/102 patients (34%) at week 12 and in 27/102 patients (26%) at the end of treatment. Virological response was sustained in 15/102 patients (15%). Ontreatment virological response was higher in previous relapsers/breakthroughs than in previous nonresponders (week 12: 49% vs. 27%, p<0.05; week 48: 46% vs. 16%, p<0.01) but no such difference was found for sustained virological response (20% vs. 12%, NS).In conclusion, triple combination treatment with daily interferon-α plus ribavirin plus amantadine for 3 months can induce virological response in a considerable number of nonresponders/relapsers to previous dual combination treatment, but the sustained virological response rate remains low.

Hepatitis C: Personalisierte Therapie

Die Fortschritte in der Therapie der Hepatitis C in den vergangenen beiden Dekaden sind bemerkenswert. Seit Beginn der antiviralen Therapie der chronischen Hepatitis C mit Standardinterferon-alpha konnte durch Kombination mit Ribavirin und Einführung des pegylierten Interferons eine kontinuierliche Verbesserung der Ausheilungsraten erreicht werden.