There are several genetic polymorphisms for the FMO3 enzyme. The effects on the metabolism of caffeine or clozapine could not be shown, indicating that the mutations have only minor functional effects or that substrate affinity is too low to be clinically relevant.

Adenovirus (Ad) E1A proteins are transcriptional regulators with antioncogenic but also transforming properties. We have previously shown that transformation-defective Ad5 E1A-derivatives are excellent tumor suppressors. For tumor-specific expression of the E1A-derivatives we intend to use tumor specific human telomerase reverse transcriptase (hTERT) core promoters. Here, we show that Spm2 and other E1A proteins with an intact amino terminus activated all hTERT constructs 10 -20-fold in malignant tumor cells but not in primary fibroblasts, without affecting the activity of endogenous telomerase. The transcription rate in tumor cells was in the range of transcription from the SV40 promoter, which qualifies an E1A-hTERT system as a putative tumor targeting/expression system. The activation of the hTERT promoter by E1A was enhanced upon deletion of the Wilms' tumor 1 negative regulatory element and maintained high after deletion of the adjacent c-Myc-responsive E-box, demonstrating an important role of the remaining sequences that contain several Sp1-motifs. E1A-mediated hTERT activation was independent from the presence of the conserved region 3 (CR3) of E1A but dependent on E1A's binding to p300/CBP and recruitment of its histone acetyltransferase activity. Moreover, E1A-Spm2 and histone deacetylase-1 behaved as antagonists with respect to the regulation of transcription from the hTERT promoter. Overall, hTERT promoter/E1A-Spm2 systems may turn out to be excellent tools for transcriptionally targeted anticancer gene therapy.

Interleukin-2 (IL-2) receptor bearing cells and soluble IL-2, measured in a bioassay with IL-2 dependent human T-cell blasts, were recognized in synovial fluid, but not in the peripheral blood of patients with rheumatoid arthritis (RA). After stimulation in vitro with appropriate concentrations of the mitogen concanavalin A (Con-A), comparable proportions of IL-2 receptor (IL-2R) bearing cells were seen in cultures of synovial fluid lymphocytes (SFL) and in cultures of peripheral blood lymphocytes (PBL). On the other hand, higher levels of secreted IL-2 were found in SFL cultures compared to corresponding PBL cultures of RA patients and normal donors. Specificity of the IL-2 bioassay was confirmed by blocking the T-cell blast proliferation (induced by SFL culture supernatants), by 83 +/- 4%, after addition of a monoclonal anti-IL-2R antibody. Despite the high levels of soluble IL-2, only a weak proliferative response was observed in the corresponding SFL cultures.

SUMMARY Mononuclear cells from peripheral blood (PBMC) of rheumatoid arthritis (RA) patients and healthy controls were incubated with α‐CD3. Cytokine secretion from 2h to 72 h of incubation was measured by ELISA, There were no significant differences in secretion of T cell derived IL‐2 and IL‐4 in cultures from RA patients and controls. The macrophage‐derived cytokines, IL‐1β and tumour‐necrosis factor‐α (TNF‐α) were secreted with a steep increase of concentration during the first 16 h of incubation by PBMC from RA patients. PBMC from healthy controls secreted both cytokines at a constantly rising rate with a maximum for TNF‐α at 48 h and for IL‐1β at 72 h. Interferon‐γ (IFN‐γ) is secreted in significantly reduced concentrations by PBMC from untreated RA patients compared with controls. Gold‐salt treatment led to a slightly delayed and enhanced secretion of TNF‐α and IL‐1β, an enhanced secretion of IL‐2 and a restored secretion of IFN‐γ.