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Cytokines are and may be used as therapeutic targets in cancer therapy. In breast cancer, interleukin (IL)-6 is associated with different features of tumor biology like metastasis, certain stages, and decreased survival. It is now an established fact that signaling via the soluble IL-6 receptor (sIL-6R) («transsignaling») is an important process in the IL-6 machinery.In this mini-review, we discover that published knowledge about sIL-6R serum levels in breast cancer patients is sparse and, furthermore, most in vitro data merely show that tumor cells produce the sIL-6R endogenously.Therefore, a lot of research is still necessary to analyze the significance of the sIL-6R and therefore the transsignaling process in breast tumors. More knowledge about the sIL-6R in breast cancer would give insights into its putative role as blood marker of active tumor disease. Secondly, the sIL-6R may be useful in breast cancer as a new therapeutic pathway. If, as suggested by the literature, IL-6 mediates the aggressiveness and the growth of breast tumors, elevated circulating levels of IL-6 and its receptor may identify patients for whom the IL-6 complex is a therapeutic target.In der Krebstherapie stellen Zytokine therapeutische Angriffsziele, sogenannte Targets, dar. Beim Mammakarzinom ist ein hoher Interleukin (IL)-6-Gehalt mit verschiedenen Tumorcharakteristika wie z.B. Metastasierung, bestimmten Stadien und vermindertem Überleben assoziiert. In der Zwischenzeit hat sich herausgestellt, dass die Signalweiterleitung über den löslichen IL-6-Rezeptor (sIL-6R) (“Transsignaling”) von großer Bedeutung innerhalb des IL-6-Geschehens ist.In diesem Mini-Review stellen wir fest, dass das publizierte Wissen über den Serumgehalt an sIL-6R bei Mammakarzinompatienten lückenhaft ist. Des Weiteren zeigen publizierte In-vitro-Daten lediglich die Tatsache, dass Tumorzellen selber den sIL-6R produzieren.Aus diesem Grunde erscheint es uns notwendig herauszufinden, welche Bedeutung der sIL-6R, und damit einhergehend der Transsignaling-Prozess, beim Mammakarzinom hat. Ein breiteres Wissen über den sIL-6R beim Brustkrebs könnte seine Rolle als eventueller Marker des aktiven Tumorgeschehens beleuchten und eine neue therapeutische Möglichkeit darstellen, zumindest für diejenigen Patienten, deren Serumgehalte an IL-6 und/oder sIL-6R erhöht sind.

Besides hepatic P450 (cytochrome P450) metabolism, there is increasing interest in the possibility of intratumoral activation of oxazaphosphorines by P450. Therefore, we investigated the expression of P450 (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) by RT (reverse transcriptase)-polymerase chain reaction (PCR) and of CYP2C9 by Western blotting in 10 different breast tumor samples. Since P450 may be down regulated by interleukin (IL) IL-6, the receptor (R) for IL-6 was analyzed by RT-PCR and IL-6 in supernatants was calculated from ELISA data. None of the breast tumors was positive for CYP2C18 and CYP2C19 mRNA, whereas CYP2C8 and CYP2C9 were detected in all 10 breast tumors. Correspondingly, all breast tumors tested (9 of 10) revealed low, but nevertheless positive, staining of the CYP2C9 protein. All 10 samples were positive for the IL-6 receptor mRNA. ELISA measurement of IL-6 cytokine in supernatants revealed that all measured samples (8 of 10) were producing IL-6, the amounts ranging from 0.004 to 3.1 ng/g(tumor tissue). In summary, we have demonstrated that tumors of the breast express two out of four members of the CYP2C family, indicating that activation of such prodrugs as oxazaphosphorines may take place intratumorally. The presence of the IL-6 receptor and of IL-6 cytokine, which is produced in an autocrine manner, opens up the possibility that the well-known down regulating effect of IL-6 also takes place in breast tumors and might explain the weak or even absent expression of different CYP2C members.

Ifosfamide is a prodrug that requires bioactivation by cytochrome P450 for antitumour activity. Up to now, little is known, to what extent in addition to the liver the ifosfamide metabolism may occur intratumorally. For this purpose, we investigated the expression of CYP3A4, CYP2C9 and CYP2B6 in breast cancer tissue using Western Blotting. Ifosfamide turnover was determined by detection of metabolites of the ifosfamide 4-hydroxylation and N-dechloroethylation in tumour microsomal incubations using HPLC/UV and LC/MS. The results demonstrate that all mammary tumours (n=11) reveal CYP3A4 expression; contents varied from 0.5 to 63 pmol mg(protein)(-1). CYP2C9 (n=9) was present in all tested breast tumour samples, too, while CYP2B6 (n=10) protein could not be detected. All measured breast cancer microsomes (n=4) showed an ifosfamide N-dechloroethylation capacity in the range from 0.04 to 0.21 pmol min(-1) mg(protein)(-1), while metabolites of the 4-hydroxylation could not be determined. In conclusion, the detected presence of CYP3A4 and CYP2C9 in breast tumours offers the possibility of intratumoral turnover of ifosfamide. For the first time in the literature, we could demonstrate a turnover of ifosfamide by microsomal preparations from human breast cancer tissue. A calculated modulation of intratumoral ifosfamide turnover could considerably influence its therapeutic efficiency.

The cytokine interleukin (IL)-1 is known to be involved in angiogenesis and metastasis. A prerequisite for IL-1 signalling is the presence of its receptor. Previously we have shown that glioblastoma cells express the IL-1 receptor type I (IL-1RI). In this study we analysed 11 breast tumour specimens for IL-1RI expression using the reverse transcriptase (RT) polymerase chain reaction (PCR). We found all the 11 breast tumours were positive for IL-1RI. This suggests that paracrine or autocrine produced IL-1 mediated signalling via IL-IRI might take place in breast tumours to control the production of pro-tumourigenic factors such as angiogenic factors and support further progression of tumour growth and metastasis.

Malignant gliomas are frequent and the prognosis is poor. The cytokine interferon gamma (IFN-gamma) enhances several immune phenomena and may be used in immunotherapy of tumours. Therefore we investigated the influence of IFN-gamma on human cell lines T98G, U87MG, 86HG39 and 85HG66, measuring cell viability (MTT-test) and proliferation (3H-thymidine uptake). IFN-gamma markedly decreased viability and proliferation of all investigated cell lines. Expression of CD44 and adhesion to hyaluronic acid (HA) are involved in glioma invasion. Influence of IFN-gamma on these two features has also been investigated. IFN-gamma markedly decreased HA-adhesion in all three investigated cell lines, whereas CD44 expression remained uninfluenced. To summarise, IFN-gamma strongly decreased cell growth and HA-adhesion of malignant glioma cell lines in vitro. We suggest further investigations to characterise better the role of IFN-gamma as a treatment opportunity for malignant gliomas.

The pathogenetic role of the central serotonin transporters (SERT) in obsessive-compulsive disorder (OCD) has been investigated in vivo by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) studies with inconsistent results. This might reflect methodological differences but possibly also the pathophysiological heterogeneity of the disorder, i.e. the age at onset of OCD. The aim of our study was to compare the SERT availability in patients with OCD to healthy controls (HC) taking into account the onset type, other factors and covariates (e.g. SERT genotype, age, depression level, gender). We studied 19 drug-naïve OCD patients (36±13 years, 8 females) with early onset (EO-OCD, n=6) or with late onset (LO-OCD, n=13), and 21 HC (38±8 years, 9 females) with PET and the SERT-selective radiotracer [11C]DASB. Statistical models indicated that a variety of covariates and their interaction influences SERT availability as measured by distribution volume ratios (DVR). These models revealed significant effects of onset type on DVR with lower values in the LO-OCD (starting at an age of 18 years) compared with EO-OCD and HC in limbic (e.g., the amygdala), paralimbic brain areas (the anterior cingulate cortex), the nucleus accumbens and striatal regions, as well as borderline significance in the thalamus and the hypothalamus. The putamen, the nucleus accumbens and the hypothalamus were found with significant interaction between two SERT gene polymorphisms (SERT-LPR and VNTR). These findings suggest that late but not early onset of OCD is associated with abnormally low SERT availability. In part, functional polymorphisms of the SERT gene might determine the differences.

It is now clear that inflammation and cancer initiation and progression are linked. Interleukin-6 (IL-6) is a pleiotropic inflammatory cytokine with described cancer stimulatory and also cancer inhibitory properties. The study’s aim was to assess the potential of circulating IL-6 as a prognostic indicator in colorectal cancer. A literature search was conducted using PubMed, restricted to articles published in English language. We compared published results in regard to differences in IL-6 levels between healthy controls and colon cancer patients (seven published results), between patients with increasing tumor stages (eight published results), between patients with differences in tumor size (four published results), and between patients with and without liver (three published results) or lung metastasis (one published result). Furthermore, we reviewed the literature in regard to the possible correlation of IL-6 levels with survival time (five published results) and correlation of IL-6 levels and lymph node involvement (three published results). Concerning colon tumors, results are consistent. Colon cancer patients reveal higher serum IL-6 levels than healthy controls. Furthermore, higher IL-6 levels are associated with increasing tumor stages and tumor size, with metastasis and decreased survival. Therefore, circulating IL-6 might be prognostic indicator in colorectal cancer.

Malignant gliomas continue to be a therapeutic challenge. One of the major problems is the early and rapidly infiltrating tumor growth. The role of the insulinlike growth factor (IGF) system in the progression of malignant glioma growth is poorly understood. In this study we investigated the expression of different members of the IGF system in malignant glioma cells and the influence of IGF-I and -II on the proliferation and migration of human glioma cell lines in vitro.Expression of IGF-I and -II, IGF-receptor I and II and IGF binding proteins (IGFBP) 1 to 6 was analysed by PCR in cell lines T98G, A172, 86HG39 (glioblastoma multiforme) and U87MG (anaplastic astrocytoma). To investigate effects on cell-proliferation, the cells were treated with IGF-I or -II (0.001-100 ng/ml). The cell viability was assessed by MTT-assay. For testing migratory effects, the Boyden-chamber-assay with different combinations of IGF-I or -II or fetal calf serum (FCS) as chemotactic agents was used.All cell lines expressed IGF-I- and IGF-II-receptor, whereas none of the cells expressed IGF-I or -II. IGFBP 2-6 were found in all cell lines. IGF-I treated cell lines T98G and 86HG39 showed a weak dose-independent enhanced proliferation compared to controls, whereas A172 did not respond. None of the investigated cell lines changed proliferation when treated with IGF-II. All IGF-I (100 ng/ml) treated cells showed increased migration compared to controls. This effect was markedly enhanced by supplementation with 0.5% FCS. Again, IGF-II had no effect.These data demonstrate that IGF-I modulates proliferation and strongly stimulates migration of glioma cell lines in vitro.

On target cells, interleukin-6 (IL-6) interacts with its receptor complex consisting of the membrane-bound IL-6 receptor (IL-6R) and the signal transducing protein gp130. IL-6R can exist as a soluble protein (sIL-6R), which binds the ligand IL-6. This soluble complex can bind to gp130 on cells that lack the membrane-bound IL-6R and initiate signaling. This process is named transsignaling. The significance of transsignaling via sIL-6R is underlined by different publications and exceeds very probably the significance of the membrane-bound IL-6R. It is the general assumption that sIL-6R acts as an agonist in combination with IL-6 resulting in an enhancement of the IL-6 effects. In this article, we suppose 'non-agonistic' properties. There are several publications that give reasons to speculate that sIL-6R (a) has IL-6-antagonistic effects, (b) has orphan properties and (c) interacts with yet unknown binding partners different from IL-6. Knowledge about additional properties of sIL-6R will enlarge the biologic understanding of this molecule and might give an explanation for the sometimes contrasting effects of the cytokine IL-6.

Cytokines are factors that are known to have both tumor-promoting and inhibitory effects on breast cancer growth depending presumably on their relative concentrations and the presence of other modulating factors. Different cytokines play an important role in controlling the immune system. Interleukin-6 (IL-6) is a pleiotropic cytokine with obviously tumor-promoting and tumor-inhibitory effects. Here, we review the role of IL-6 in in vitro experiments of breast tumor cells, in breast tumor tissues (BTs) and assess its potential as a prognostic indicator in breast cancer patients. A literature search was conducted using PubMed, restricted to articles published in English language. In summary, results regarding the effect of IL-6 on breast tumor cells and on BTs are not unique indicating both tumor-promoting and inhibitory effects of IL-6. Concerning patients' serum IL-6 levels, data are surprisingly unique showing IL-6 to be a negative prognosticator in breast tumor patients.

The oxazaphosphorines cyclophosphamide (CP) and ifosfamide (IF) are alkylating agents that require bioactivation via cytochrome (CYP) P450 isoenzymes including CYP2C9 enzymes. The present study investigated CYP2C9 in regard to its allelic variants in 23 tumor samples (10 breast tumors, 1 breast tumor cell line, 5 brain tumors, 7 glioma cell lines) with restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The mutant alleles of CYP2C9 were residue 144 (Arg (*1)/Cys (*2)), residue 358 (Tyr/Cys), residue 359 (Ile/Leu (*3)) and residue 417 (Gly/Asp). The frequencies of the CYP2C9*1, CYP2C9*2 and CYP2C9*3 alleles in the cancer samples examined were found to be 0.848, 0.152 and 0.043, respectively. No sample revealed a mutation at residue 358 or 417. Comparing breast with brain tumors, brain tumors seemed to reveal a higher incidence of heterozygotes (5/12 compared to 2/11) at residue 144 and, with regard to residue 359, a lower incidence of heterozygotes (0/12 compared to 2/11). In summary, our data indicate that in tumor material, as in healthy material, the same allelic variants of CYP2C9 occur. Compared to healthy tissue, tumor material seemed to reveal a higher incidence of the *2 allele, but a significant difference could not be established. Our results show that brain and breast tumor samples appeared to differ in their frequency of heterozygotes at residues 144 and 359. This might also have an impact on intratumoral oxazaphosphorine metabolism.