Circulating endothelial progenitor cells in castration resistant prostate cancer: a randomized, controlled, biomarker study.

BACKGROUND: Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients. PATIENTS AND METHODS: Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m2) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy. RESULTS: A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6-3.6 months, 95% CI) and 6.2 months (4.9-7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable. CONCLUSION: In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS. TRIAL REGISTERY: clinicaltrialsregister.eu EudraCT 2007-003705-27.

TUSC3 loss alters the ER stress response and accelerates prostate cancer growth in vivo.

Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.

Formation of sex hormone transients resulting from attack of free radicals.

BACKGROUND: Transients of the sex hormones testosterone (TES) and estrone (E1) exhibit an impact on the carcinogenesis of most prostate and breast cancer types. For elucidation of involved reaction mechanisms, in vitro, experiments using γ-ray for generation of attacking hormone transients and UV-light (λ=254 nm) for excitation of hormone molecules were applied. Materials and Methods. Experiments in vitro (Escherichia coli AB1157) incubated with TES and E1, individually as well as in mixture with vitamin C (electron donor), were performed under γ-irradiation in water-alcohol (40/60) medium for clarifying-up the reaction mechanism. The hormone degradation/regeneration processes were studied by high performance liquid chromatography analysis. RESULTS: Independently of hormone molecular structure, the determining factor for the biological properties, such as carcinogenity, were found to be based on the hormone transients. The biological ability of these, however, depends on the chemical properties of the species attacking the corresponding hormone. Hormone degradation can be, at least partly, converted into hormone regeneration by electron transfer from an electron donor (e.g. vitamin C), when available during the period of status nascendi of the hormone radicals.

Photo-induced regeneration of hormones by electron transfer processes: Potential biological and medical consequences.

Based on the previous results concerning electron transfer processes in biological substances, it was of interest to investigate if hormone transients resulting by e.g. electron emission can be regenerated.The presented results prove for the first time that the hormone transients originating by the electron emission process can be successfully regenerated by the transfer of electrons from a potent electron donor, such as vitamin C (VitC). Investigations were performed using progesterone (PRG), testosterone (TES) and estrone (E1) as representatives of hormones. By irradiation with monochromatic UV light (λ=254 nm) in a media of 40% water and 60% ethanol, the degradation as well as the regeneration of the hormones was studied with each hormone individually and in the mixture with VitC as a function of the absorbed UV dose, using HPLC. Calculated from the obtained initial yields, the determined regeneration of PRG amounted to 52.7%, for TES to 58.6% and for E1 to 90.9%. The consumption of VitC was determined in the same way.The reported results concerning the regeneration of hormones by the transfer of electrons from an electron donor offer a new, promising method for the therapy with hormones. As a consequence of the regeneration of hormones, a decreased formation of carcinogenic metabolites is expected.

The effect of progesterone on the electron emission and degradation of testosterone.

Based on recent findings that hormones can emit electrons () from their excited singlet state in polar media, it was of importance to study a possible mutual interaction of progesterone (PRG) and testosterone (TES) in this respect. Hormones of highest purity were dissolved in an air-free mixture of 40% triply distilled water and 60% ethanol, because the hormones are unsoluble in water. As energy source for substrate excitation in singlet state served a monochromatic UV-light (254 nm), the emitted electrons were scavenged by chloroethanol, whereby the quantum yield of produced Cl⁻ ions, Q (Cl⁻), is equal to Q(e⁻(aq)). Hormone degradation initiated by the electron emission was studied by HPLC method, using a Zorbax Eclipse XDB-C18 column (150 mm x 4.6 mm, 5 µm). The quantum yield of emitted e⁻(aq), Q(e⁻(aq)), from TES was 3.6 times higher than that from PRG, which is explained by the different molecular structures of the hormones. Observed 2nd and 3rd maxima of electron emission indicate the ability of TES and PRG products to also eject e⁻(aq), but with lower yield. It can be stated that a part of the emitted electrons from TES are consumed by PRG⁺ leading to a partial regeneration of hormone. The present results offer a deeper insight in the biological behavior of hormones.

Electron emission and product analysis of estrone: progesterone interactions studied by experiments in vitro.

Recent studies showed that hormones like progesterone, testosterone, etc. can eject [Formula: see text] (solvated electrons). By means of electron transfer processes via the brain, the hormones communicate with other biological systems in the organism. The present study proves that also estrone is able to emit electrons. Their yield strongly depends on the concentration of the hormone, temperature and on the absorbed energy. The metabolites resulting from this process are likewise able to generate electrons, however with much smaller yields. The formation of the estrone metabolites is studied by HPLC-analyses. In vitro experiments with MCF-7 cells demonstrate the distinct effect of progesterone on the carcinogenity of estrone metabolites. Probable reaction mechanisms for explanation of the observed effects are postulated.

Metabolite formation of 17alpha-hydroxyprogesterone as a consequence of e⁻(aq)-emission and progesterone effect regarding cancer.

Based on previous investigations on several hormones, 17α-hydroxyprogesterone (17α-HOPRG) was studied in respect to cancer initiation by its metabolites resulting from electron emission. The emission of electrons (e⁻(aq)) from its singlet excited state of 17α-HOPRG and HPLC-analysis of products were studied. Possible carcinogenicity of metabolites originating from 17α-HOPRG and the effect of progesterone (PRG) in this respect were studied in vitro. The results showed that 17α-HOPRG is very sensitive towards oxygen. The highest Q(e⁻(aq)) values were obtained by dissolution and UV-irradiation of substrate in airfree media. 17α-HOPRG metabolites showed a strong anticancer activity, which is, however, lower compared to that of PRG-metabolites. Mixture of both hormones, 17α-HOPRG and PRG, in respect to carcinogenicity showed a synergistic effect of PRG on 17α-HOPRG. Reaction mechanisms are presented.

Mutual interaction of 17beta-estradiol and progesterone: electron emission. Free radical effect studied by experiments in vitro.

BACKGROUND: Based on the different behaviour of 17beta-estradiol (17betaE(2)) and progesterone (PRG), it was of interest to investigate the interaction of both hormones in respect of their electron emission and cytotoxicity by experiments in vitro. MATERIALS AND METHODS: The studies include determination of emitted electrons (e(-)(aq)) by the individual hormones as well as by their mixtures, all complexed with cyclodextrin (HBC). Experiments in vitro (Escherichia coli bacteria) were performed for a better understanding of the mechanisms involved. Survival ratios, DeltaD(37)(Gy), were calculated. RESULTS: Aqueous HBC as well as 17betaE(2) and PRG, individually as well as in mixtures, are able to emit e(-)(aq). The resulting transients can lead to the formation of metabolites, some of which can initiate cancer. It was established that both hormones, 17betaE(2) and PRG, interact in respect to their electron emission property. In the frame of experiments in vitro, it was found that oxidizing radicals (OH, O(2)(-)) lead to negative DeltaD(37)(Gy) values, indicating cytostatic properties. On the other hand, the primary reducing radicals (e(-)(aq), H) lead to positive DeltaD(37)(Gy) values, indicating a radical-scavenging effect. CONCLUSION: The main outcome of this work is that PRG in combination with 17betaE(2) can strongly reduce the number of carcinogenic 17betaE(2)-metabolites. This fact offers a new pathway for application of hormones in medical treatment of patients.

17beta-estradiol acting as an electron mediator: experiments in vitro.

BACKGROUND: The present work reports on the effect of oxidizing (OH, O(2)(*-)) and reducing free radicals (e(-)(aq), H) on 17beta-estradiol (17betaE2) in respect to breast cancer initiation. The objectives of the study were based on the following premise: the ability of 17betaE2 to emit electrons (e(-)(aq)) as well as to transfer them to other biological systems. Thereby, the resulting transient hormone products are leading to the formation of metabolites, some of which may initiate the neoplastic process. The present work considers the effect of the simultaneously generated oxidizing and reducing free radicals on the carcinogenic properties of the 17betaE2 metabolites. MATERIALS AND METHODS: Water-soluble 17betaE2 with incorporated 2-hydroxypropyl-beta-cyclodextrin (HBC) in various aqueous media (pH ~7.4), saturated with air, N(2)O or argon, as well as HBC alone, were exposed to the action of free radicals produced by gamma-ray. Escherichia coli bacteria (AB 1157) were used as a model for living systems. RESULTS: From the survival curves obtained under different conditions, the derived DeltaD(37) values (representing the radiation dose at which N/N(0)=0.37; N/N(0) ratio: N(0)=starting number of colonies, N=number after irradiation treatment) illustrate that 17betaE2 as well as HBC act as very powerful scavengers of OH and O(2)(*-) radicals. On the other hand, 17betaE2 and HBC intermediates resulting from attack of the reducing species (e(-)(aq), H) have strong anticancer properties. CONCLUSION: It is stated that DeltaD(37) values strongly depend on the reactivity of the individual free radicals. Oxidizing free radicals lead to positive DeltaD(37) values, illustrating the strongly pronounced radiation protecting ability of the systems. On the contrary, the primary reducing free radicals result in negative DeltaD(37) values, indicating anticancer effect.

Thyrotropin serum concentrations in patients with papillary thyroid microcancers.

BACKGROUND: Recent studies have shown that elevated serum thyrotropin (thyroid-stimulating hormone [TSH]) concentrations are associated with an increased risk of differentiated thyroid cancers in patients with nodular goiter. Therefore, the measurement of TSH concentrations might support the clinical estimation of cancer risk, especially in patients with thyroid nodules that are too small for fine-needle aspiration biopsies. Thus, the objective of this study was to compare preoperative serum TSH concentrations in patients with papillary thyroid microcarcinoma (PTMC) and individuals in whom the presence of even small differentiated thyroid cancers was excluded by thorough histological examination of the thyroid after total thyroidectomy because of medullary thyroid carcinoma or c-cell hyperplasia. METHODS: The study was a retrospective cross-sectional analysis. Thirty-three patients with PTMC who had undergone a hemi- or total thyroidectomy and 54 subjects with medullary thyroid carcinoma or c-cell hyperplasia in whom a total thyroidectomy had been performed between 1994 and 2008 were included. Exclusion criteria were the intake of medication that might affect thyroid function and previous thyroid cancer or thyroid surgery. RESULTS: The mean TSH value was comparable between patients with PTMCs (1.40 +/- 0.92 mLU/L, 95% CI = 1.07-1.72) and the control group (1.43 +/- 1.44 mLU/L; 95% CI = 1.04-1.82, p = 0.912). There was a positive trend in correlation between nodule size and TSH levels in patients with PTMC (p = 0.066). CONCLUSIONS: TSH is not elevated in subjects with PTMCs, indicating that it is not likely involved in the de novo oncogenesis of these small cancers. However, TSH might rather play a role in the progression of preexisting PTMCs.

The 4-hydroxyestrone: Electron emission, formation of secondary metabolites and mechanisms of carcinogenesis.

4-Hydroxyestrone (4-OHE(1)), a typical cancer-inducing metabolite, originating from 17beta-estradiol (17beta-E2), was chosen as a model for the studies. The aim was to get a deeper insight in the mechanisms of its ability to initiate cancer. It was found, that 4-OHE(1) can eject electrons (e(aq)(-)), when excited in the singlet state by monochromatic UV-light (lambda=254 nm) in polar media (water:ethanol=40:60 vol.%). The quantum yield Q(e(aq)(-)), determined for various 4-OHE(1) concentrations, is found to be as high as that previously observed for 17beta-E2. It decreases with increasing substrate concentration, but it is enhanced at higher temperature. The ability of 4-OHE(1) to eject as well as to consume and to transfer electrons to other biological systems, classifies it as an electron mediator, similar to 17beta-E2. The 4-OHE(1) transients resulting of the electron emission process are leading to the formation of secondary metabolites. Surprisingly, it was established that the secondary metabolites possess likewise the ability to eject as well as to consume electrons. Hence, they behave similar like 17beta-E2. However, the structure of the secondary formed metabolites, which determinates their biological properties and carcinogenity, depends on the nature of the available reaction partners involved in their formation. A probable reaction mechanism explaining the subject matter is discussed.