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M Andreeff

Publications and source records attributed to M Andreeff.

At least 19 recordsLinked to original sources
PubMed2006

Differential tumor suppressor properties and transforming growth factor-beta responsiveness of p57KIP2 in leukemia cells with aberrant p57KIP2 promoter DNA methylation.

To investigate if the tumor suppressor properties of p57KIP2 are dependent on its DNA methylation status, we studied the impact of several stress stimuli in leukemic cell lines with different p57KIP2 promoter DNA methylation levels. p57KIP2 reactivation was observed after stimulation with transforming growth factor-beta, other cytokines, high-density culture or serum withdrawal in p57KIP2 promoter unmethylated cells but not in methylated cells. In these cells, p57KIP2 reactivation required the use of a hypomethylating agent or a histone deacetylase inhibitor. Overexpression of p57KIP2 in p57KIP2 promoter methylated leukemic cell lines resulted in cell growth arrest and the induction of apoptosis. In contrast, overexpression of p57KIP2 in partially methylated cells only resulted in a moderate inhibition of cell growth and had no impact on apoptosis. Transduction of unmethylated cells expressing high levels of p57KIP2 with p57KIP2 short hairpin RNA resulted in increased cell proliferation. These results suggest that the tumor suppressive properties of p57KIP2 in leukemia may depend on the intrinsic promoter DNA methylation status of the gene.

Apoptosis↗
PubMed2006

Vaccination with leukemia cells expressing cell-surface-associated GM-CSF blocks leukemia induction in immunocompetent mice.

The fundamental basis for immunotherapy of leukemia is that leukemic cells express specific antigens that are not expressed by normal hematopoietic cells. However, the host immune system appears to be tolerant to leukemia cells. To overcome this tolerance, we vaccinated immunocompetent mice with murine leukemia cells (WEHI-3B and BCR-ABL+ 32D cells) transduced with a specifically constructed transmembrane form of granulocyte-macrophage colony-stimulating factor (tmGM-CSF). The transduced cells expressed tmGM-CSF on the cell-surface. To determine whether tmGM-CSF-expressing WEHI-3B leukemia cells would prevent leukemia formation as a vaccine, immunocompetent mice (BALB/c and C3H/HEJ) were immunized with lethally irradiated murine leukemia cells expressing cell-surface tmGM-CSF before challenging mice with murine leukemia cells. Two immunocompetent mouse models were investigated, either WEHI-3B cells in BALB/c mice or BCR-ABL+ 32D cells in C3H/HEJ mouse. The results showed that 100% of WEHI-3B/tmGM-CSF-vaccinated BALB/c mice and about 65% of 32D+ BCR-ABL/tmGM-CSF-vaccinated C3H/HEJ mice were protected from leukemia after leukemia cell challenge, whereas all non-vaccinated mice succumbed to leukemia. Spleen and marrow cell suspensions from vaccinated mice challenged with WEHI-3B cells lacked detectable GFP+ WEHI-3B cells at 82 days post-challenge. A significant delay of death was observed in C3H/HEJ mice challenged with the very aggressive DA-1 cell line expressing BCR-ABL. Vaccination of mice with WEHI-3B/CD40L cells protected 80% of the mice from the WEHI-3B challenge. Notably, 60% of the WEHI-3B/BALB/c mice were also protected from leukemia when WEHI-3B/tmGM-CSF vaccination was carried out after the leukemia challenge. In order to determine whether cellular immunity is involved in this vaccine-mediated protection, either CD4+ or CD8+ T cells were depleted from mice after the WEHI-3B/tmGM-CSF vaccination. The results indicate that CD8+ T-cells mediated the protective immune response provided by the irradiated tmGM-CSF-expressing WEHI-3B cells. In addition, vaccination of nude mice did not provide protection from WEHI-3B leukemia induction. Importantly, 80% of non-vaccinated mice were also protected from a WEHI-3B cell challenge after receiving spleen cells from vaccinated mice 1 day before challenge with leukemia cells. These results indicate that overexpression of tmGM-CSF on the leukemia cell-surface can enhance the recognition of leukemic cells by CD8+ T cells, and can either prevent or significantly delay leukemia induction. These findings suggest that injection of irradiated leukemia cells expressing cell-surface-bound GM-CSF has the potential as an immunological approach to treat leukemia.

Animals↗
PubMed2006

Apoptosis effector mechanisms: a requiem performed in different keys.

Apoptosis is the regulated form of cell death utilized by metazoans to remove unneeded, damaged, or potentially deleterious cells. Certain manifestations of apoptosis may be associated with the proteolytic activity of caspases. These changes are often held as hallmarks of apoptosis in dying cells. Consequently, many regard caspases as the central effectors or executioners of apoptosis. However, this "caspase-centric" paradigm of apoptotic cell death does not appear to be as universal as once believed. In fact, during apoptosis the efficacy of caspases may be highly dependent on the cytotoxic stimulus as well as genetic and epigenetic factors. An ever-increasing number of studies strongly suggest that there are effectors in addition to caspases, which are important in generating apoptotic signatures in dying cells. These seemingly caspase-independent effectors may represent evolutionarily redundant or failsafe mechanisms for apoptotic cell elimination. In this review, we will discuss the molecular regulation of caspases and various caspase-independent effectors of apoptosis, describe the potential context and/or limitations of these mechanisms, and explore why the understanding of these processes may have relevance in cancer where treatment is believed to engage apoptosis to destroy tumor cells.

Animals↗
PubMed2006

Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C.

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a new anticancer agent currently in clinical trials. The ability of 17-AAG to abrogate the function of heat-shock protein Hsp90 and modulate cellular sensitivity to anticancer agents has prompted recent research to use this compound in drug combination therapy. Here we report that 17-AAG has striking opposite effects on the activity of arsenic trioxide (ATO) and ara-C. Combination of 17-AAG with ATO exhibited a synergistic effect in leukemia cells, whereas coincubation of 17-AAG and ara-C showed antagonistic activity. Mechanistic studies revealed that ATO exerted cytotoxic action by reactive oxygen species generation, and activated Akt survival pathway. 17-AAG abrogated Akt activation and enhanced the activity of ATO. In contrast, treatment of leukemia cells with 17-AAG caused a G1 arrest, a decrease in DNA synthesis and reduced ara-C incorporation into DNA, leading to antagonism. The ability of 17-AAG to enhance the antileukemia activity of ATO was further demonstrated in primary leukemia cells isolated from patients with acute myeloid leukemia and chronic lymphocytic leukemia, including cells from refractory patients. Our data suggest that combination of 17-AAG and ATO may be an effective therapeutic regimen. Caution should be exercised in using 17-AAG together with ara-C, as their combination effects are schedule dependent.

Acute Disease↗
PubMed2005

The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells.

Development of novel therapeutic strategies is a continuing challenge for the treatment of acute myeloid leukemia (AML). The novel triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid (CDDO-Me), induces apoptosis in myeloid leukemic cell lines and in primary AML samples. In this report, the effects of CDDO-Me on CD34(+) AML progenitor cells in vitro were examined. CDDO-Me induced apoptosis in all but one of ten AML samples. CDDO-Me is known to inhibit the activation of ERK1/2. In this series of primary AML samples, ERK was expressed and phosphorylated in all patient samples studied and CDDO-Me inhibited ERK phosphorylation in five of 10 samples. However, CDDO-Me induced apoptosis in four of five samples without decreasing pERK levels, suggesting that pERK is not the sole target of the compound. CDDO-Me induced phosphorylation of p38 in AML-derived U937 cells. Pretreatment of U937 cells with a p38 inhibitor protected cells from the cyto-toxic effects of CDDO-Me. These findings suggest a role for p38 in CDDO-Me-induced apoptosis. In preliminary studies, CDDO-Me induced p38 phosphorylation in seven of eight primary AML samples. These findings suggest that CDDO-Me treatment shifts cell signaling away from cyto-protective pathways and thus CDDO-Me may be effective for the treatment of AML.

Acute Disease↗
PubMed2005

Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia.

We investigated the constitutive activation of the MEK/ERK pathway in acute myelogenous leukemia (AML) via a flow cytometric technique to quantitate expression of phosphorylated ERK (p-ERK). A total of 42 AML samples (16 newly diagnosed, 26 relapsed/refractory) were analyzed. Normal bone marrow CD34+ cells (n = 10) had little or no expression of p-ERK, while G-CSF-mobilized CD34+ cells exhibited enhanced p-ERK levels. Markedly elevated p-ERK levels were found in 83.3% of the AML samples, with no differences observed between the newly diagnosed and relapsed/refractory samples. Treatment with a MEK inhibitor resulted in significantly decreased p-ERK levels in both the newly diagnosed and relapsed/refractory samples, which was associated with growth arrest, but not apoptosis induction. In summary, we defined conditions for the analysis of MAPK signaling in primary AML samples. Normal CD34+ cells expressed very low levels of p-ERK, and increased p-ERK levels were found in normal G-CSF-stimulated circulating CD34+ cells. Constitutively high p-ERK levels observed in the majority of AML samples suggest deregulation of this pathway that appears to be independent of disease status. The ability of ERK inhibition to promote growth arrest rather than apoptosis suggests that clinical trials of MEK/ERK inhibitors may be more effective when combined with chemotherapy.

Acute Disease↗
PubMed2005

Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation.

Anaplastic large-cell lymphoma (ALCL) is a heterogeneous lymphoma category in which a subset of cases carry the t(2;5)(p23;q35) or variant translocations resulting in overexpression of anaplastic lymphoma kinase (ALK). LY293111 (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]-phenoxy] benzoic acid sodium salt) is a leukotriene B4 receptor antagonist, which was found to be safe and tolerable in Phase I clinical trials. In this study, we investigated the potential therapeutic effects and mechanisms of action of LY293111 in ALCL cell lines. LY293111 inhibited proliferation of both ALK(+) and ALK(-) ALCL cell in a dose-dependent fashion and induced complete G(1)-S cell cycle arrest, which was accompanied by upregulation of p27 and downregulation of cyclin E. Pretreatment with LY293111 for 4 h resulted in profound inhibition of serum-induced phosphorylation of extracellular-regulated kinases-1 and 2 and Akt and a concomitant increase in the phosphorylation of the stress-activated kinase c-jun N-terminal kinases (JNK). Simultaneously, LY293111 induced caspase-dependent apoptosis via activation of the intrinsic pathway, including early loss of mitochondrial inner transmembrane potential and the production of reactive oxygen species (ROS), cleavage of caspases-9, -3, poly ADP-ribose polymerase (PARP) and X-linked inhibitor of apoptosis. The phospho-JNK inhibitor SP600125 partially protected Sup-M2 cells from LY293111-induced apoptosis, PARP cleavage and ROS generation, suggesting a role for JNK in LY293111-induced cell death. These results warrant further studies of LY293111 in ALCL.

Apoptosis↗
PubMed2005

[beta-Radiation exposure with (188)Re-labelled pharmaceuticals].

AIM: The number of therapies with radiopharmaceuticals labelled with (188)Re is increasing requiring the documentation of the beta radiation exposure Hp(0.07) of the staff at all working and production sites and during the application and follow-up of the patient according to the new German Radiation Protection Law (StrlSchV). However, data for beta-radiation exposure are rare. Therefore, we determined the personal dose Hp(0.07) of the skin of the hands handling (188)Re radiopharmaceuticals to identify steps of high radiation exposure and to optimize working conditions. METHOD: Thermoluminescence dosimeters (TLD 100) were fixed to the fingertips of the radiochemist, the physician and the nurse and compared to official ring dosimeters. In addition, to monitor radiation exposure continuously readable electronic beta- and gamma dosimeters EPD (Siemens) were used. At eight days in which therapies were performed these readings were evaluated. RESULTS: Considering one therapy with a (188)Re-labelled radiopharmaceutical the middle finger of the radiochemist (production) and the physician (application) showed a radiation burden of 894 and 664 muSv/GBq, respectively. The cumulative dose of the fingertips after eight days of therapy was 249 and 110 mSv for the radiochemist and physician, respectively. A cumulative finger dose after eight days of therapy of 17 and 38 muSv/GBq was found for physician and nurse leading to a Hp(0.07) of 3 and 6 mSv, respectively. Preparing the radiopharmaceutical labelled with 20GBq of (188)Re the reading of the personal electronic dosimeter of the radiochemist showed a gamma-dose rate Hp(10) of 55 muSv/h and a beta-dose rate Hp(0.07) of 663 muSv/h which are obviously not representative for the true radiation dose to the skin of the fingertips. CONCLUSION: During therapy with (188)Re-labelled radiopharmaceuticals the true radiation dose to the skin of the finger tips exceeds by far the readings of the official ring dosimeters as well as the continuously readable beta- and gamma dosimeters. This means a risk in exceeding the radiation limit of 500 mSv/a given in the German Radiation Protection Law ( section sign55 StrSchV) primarily in the working field of the radiochemist and the administering physician.

Beta Particles↗
PubMed2005

Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects.

The MEK/MAPK signaling module is a key integration point along signal transduction cascades that regulate cell growth, survival, and differentiation, and is aberrantly activated in many human tumors. In tumor cells, constitutive MAPK activation affords increased proliferation and resistance to apoptotic stimuli, including classical cytotoxic drugs. In most instances, however, MAPK inhibition has cytostatic rather than cytotoxic effects, which may explain the lack of objective responses observed in early clinical trials of MEK inhibitors. Nevertheless, amenability of the MAPK pathway to pharmacodynamic evaluation and negligible clinical toxicity make MEK inhibitors an ideal platform to build pharmacological combinations with synergistic antitumor activity. In AML, the MEK/MAPK pathway is constitutively activated in the majority of cases (75%), conferring a uniformly poor prognosis; in preclinical models of AML, MEK blockade profoundly inhibits cell growth and proliferation and downregulates the expression of several anti-apoptotic players, thereby lowering the apoptotic threshold. Apoptosis induction, however, requires concentrations of MEK inhibitors much higher than those required to inhibit proliferation. Nevertheless, MEK blockade efficiently and selectively sensitizes leukemic cells to sub-optimal doses of other apoptotic stimuli, including classical cytotoxics (nucleoside analogs, microtubule-targeted drugs, gamma-irradiation), biologicals (retinoids, interferons, arsenic trioxide), and, most interestingly, other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists). In most instances, these MEK inhibition-based combinations result in a striking pro-apoptotic synergism in preclinical models. Here we briefly discuss evidence suggesting that MAPK pathway inhibition could play a prominent role in the development of integrated therapeutic strategies aimed at synergistic anti-leukemic effects.

Animals↗
PubMed2004

Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias.

The phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathway is involved in cell growth, proliferation, and apoptosis. The functional activation of PI3K/AKT provides survival signals and blockade of this pathway may facilitate cell death. Downstream targets of PI3K-AKT include the proapoptotic protein BAD, caspase-9, NF-kappaB, and Forkhead. We have previously reported that BAD is constitutively phosphorylated in primary acute myeloid leukemia (AML) cells, a post-transcriptional modification, which inactivates its proapoptotic function. In this study, we tested the hypothesis that the inhibition of PI3K by LY294002 results in the dephosphorylation of AKT and BAD, and thus promote leukemia cell apoptosis. We investigated the effects of LY294002 in megakaryocytic leukemia-derived MO7E cells, primary AML and normal bone marrow progenitor cells. In MO7E cells, LY294002 reduced AKT kinase activity, induced dephosphorylation of AKT and BAD, and increased apoptosis. Concomitant inhibition of mitogen-activated protein kinase signaling or combination with all-trans retinoic acid further enhanced apoptosis of leukemic cells. In primary AML samples, clonogenic cell growth was significantly reduced. Normal hematopoietic progenitors were less affected, suggesting preferential targeting of leukemia cells. In conclusion, the data suggest that the inhibition of the PI3K/AKT signaling pathway restores apoptosis in AML and may be explored as a novel target for molecular therapeutics in AML.

Apoptosis↗
PubMed2004

PKC alpha mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation.

Overexpression of protein kinase C alpha (PKC alpha) promotes Bcl2 phosphorylation and chemoresistance in human acute leukemia cells. The contribution of non-Bcl2 mechanisms in this process is currently unknown. In this report, overexpression of PKC alpha was found not to affect cell proliferation, cell cycle, or activation of mitogen-activated protein kinases. The failure of PKC alpha overexpression to activate non-Bcl2 survival pathways suggested that PKC alpha-mediated chemoresistance requires Bcl2. Supporting this notion, REH/PKC alpha transfectants were found to be as sensitive to HA14-1 (a drug that targets Bcl2 function) as parental cells. In addition, HA14-1 abrogated PKC alpha's ability to protect REH cells from etoposide. These findings suggested that Bcl2 is necessary for the protective function of PKC alpha in REH cells. Since Bcl2 phosphorylation status is negatively regulated by protein phosphatase 2A (PP2A) and PP2A regulates PKC alpha, we investigated whether PKC alpha can conversely regulate PP2A. Overexpression of PKC alpha was found to suppress mitochondrial PP2A activity by a mechanism that, at least in part, involves suppressed expression of the regulatory subunit comprising the Bcl2 phosphatase (ie the PP2A/B56 alpha subunit). The ability of PKC alpha to target both Bcl2 and the Bcl2 phosphatase represents a novel mechanism for chemoresistance.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Comparison of the efficiency of transduction of leukemic cells by fiber-modified adenoviruses.

Efficient gene transfer with adenoviral type 5 (Ad5) vectors depends on the initial attachment of their fiber, which binds the coxsackie-adenovirus receptor (CAR), and their subsequent internalization, mediated by the interaction of viral penton base with target cell alphav integrins. We previously demonstrated that human leukemic cells lack these receptors and are therefore resistant to Ad5 transduction, limiting efforts to genetically modify these cells. Human leukemic blasts are, however, susceptible to transduction with an adenovector made CAR independent by substitution of a chimeric Ad5/35 fiber [Yotnda et al. (2001). Gene Ther. 8, 930-937]. Other receptors can also be targeted with recombinant ligand moieties incorporated into adenovirus fiber. We have determined which of these fiber-modified adenovectors is most effective at modifying human primary leukemia cells, and lines. We used a replication-incompetent Ad5-beta-gal vector, in which the Ad5 fiber was replaced with fiber from various adenovirus serotypes (Ad35 and Ad11), or modified either with variable length polylysine (K4, K7, K21) or RGD-4C peptide. All the modified fiber vectors transduced primary leukemia cells and cell lines more efficiently than Ad5. Polylysine-substituted Ad5F/K21 and peptide-modified Ad5F/RGD vectors were most effective overall (up to 100% efficiency), whereas Ad5F/RGD was the most effective at transducing B cell acute lymphoblastic leukemia cells (90% efficiency). Ad5F/K21 and Ad5F/RGD should be of value for the genetic modification of human primary leukemia cells.

Adenoviridae↗
PubMed2003

Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL.

Acute myelogenous leukemia (AML) remains a deadly disease for most adult patients, due primarily to the emergence of chemoresistant cells. Defects in apoptosis pathways make important contributions to chemoresistance, suggesting a need to restore apoptosis sensitivity or to identify alternative pathways for apoptosis induction. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity, including 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-m). We explored the effects of CDDO and CDDO-m in vitro on established AML cell lines (HL-60, U937, AML-2) and on freshly isolated AML blasts. CDDO and CDDO-m reduced the viability of all AML cell lines tested in a dose-dependent manner, with effective doses for killing 50% of cells (ED(50)) within 48 h of approximately 1 and 0.5 muM, respectively. CDDO or CDDO-m also induced substantial increases in cell death in five out of 10 samples of primary AML blasts. Cell death induced by CDDO and CDDO-m was attributed to apoptosis, based on characteristic cell morphology and evidence of caspase activation. Immunoblot analysis demonstrated proteolytic processing of caspase-3, -7, and -8, but not caspase-9, suggesting the involvement of the 'extrinsic' pathway, linked to apoptosis induction by TNF-family death receptors. Accordingly, CDDO and CDDO-m induced concentration-dependent reductions in the levels of FLIP protein, an endogenous antagonist of caspase-8, without altering the levels of several other apoptosis-relevant proteins. Reductions in FLIP were rapid, detectable within 3 h after exposure of AML cell lines to CDDO or CDDO-m. CDDO and CDDO-m also sensitized two of four leukemia lines to TRAIL, a TNF-family death ligand. The findings suggest that synthetic triterpenoids warrant further investigation in the treatment of AML, alone or in combination with TRAIL or other immune-based therapies.

Antineoplastic Agents↗
PubMed2003

Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia.

XIAP is a member of the inhibitors-of-apoptosis family of proteins, which inhibit caspases and block cell death, with prognostic importance in AML. Here we demonstrate that cytokines regulate the expression of XIAP in leukemic cell lines and primary AML blasts. Inhibition of phosphatidylinositol-3 kinase (PI3K) with LY294002 and of the mitogen-activated protein kinase (MAPK) cascade by PD98059 resulted in decreased XIAP levels (34+/-8.7 and 23+/-5.7%, respectively). We then generated OCI-AML3 cells with constitutively phosphorylated Akt (p473-Akt) by retroviral gene transfer. Neither these nor Akt inhibitor-treated OCI-AML3 cells showed changes in XIAP levels, suggesting that XIAP expression is regulated by PI3K downstream effectors other than Akt. The induction of XIAP expression by cytokines through PI3K/MAPK pathways is consistent with its role in cell survival. Exposure of leukemic cells to chemotherapeutic agents decreased XIAP protein levels by caspase-dependent XIAP cleavage. Targeting XIAP by XIAP antisense oligonucleotide resulted in downregulation of XIAP, activation of caspases and cell death, and sensitized HL-60 cells to Ara-C. Our results suggest that XIAP is regulated by cytokines through PI3K, and to a lesser degree through MAPK pathways. Selective downregulation of XIAP expression might be of therapeutic benefit to leukemic patients.

Base Sequence↗
PubMed2003

[Beta-radiation exposure at the finger tips during the radionuclide synovectomy].

AIM: The radiation synovectomy is a widespread therapeutic option in rheumatoid arthritis. However, data for the beta-radiation exposure are rare. The aim of this study was to determine the personal dose equivalent H(P) (0.07) of the skin of the hands. METHODS: Thermo-luminescence detectors (TLDs) were attached at all fingertips of the therapist, the radiochemist and the nurse. In summary, the measurement of beta-exposure occurred in 155 joints at 6 days with different radio-nuclides ((169)Er, (186)Re, (90)Y). RESULTS: The greatest beta exposure were show at the forefinger (L-Ff) and thumb (L-Th) of the left hand, with which the therapist (right hander) fixed the injection needle. In 52 treated finger-joints (1204 MBq (169)Er), 29 treated large joints (2405 MBq (186)Re) and 15 treated knees (3100 MBq (90)Y) we found a cumulative beta exposure over all radionuclides of 190 mSv at L-Ff and 48 mSv at L-Th. The specific beta exposure for the individual radio-nuclides showed beta exposures of 0.56 mu Sv/MBq for (169)Er and 1.52 mu Sv/MBq for (186)Re-186 at the L-Ff. With using a manipulator the beta-exposure ((90)Y) could reduced from 22,09 to 0.42 mu Sv/MBq at the L-Ff. The greatest beta exposures for the radiochemist was 119 mSv at the L-Ff for all radionuclides. CONCLUSION: In usual techniques of radiation synovectomy the (90)Y produced the greatest part of radiation exposure. Especially at the L-Ff it might exceed the German limit for the official dosimetry service at the skin ( section sign 55 Strl-SchV). Using a holding forceps we can keep the legal rules and can reduce considerably the beta exposure.

Arthritis, Rheumatoid↗
PubMed2002

hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity.

We recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression and selectively kills various human cancer cells both in vitro and in xenograft tumors. However, it remains unclear whether the hTERT promoter can be used to induce transgene expression in syngenic tumors in mice and whether Bax gene expression driven by the hTERT promoter will cause long-term, stem cell-related toxicity. To address these questions, we tested hTERT promoter-driven, adenovirus-mediated Bax transgene expression in an established syngenic mouse tumor model and its effects on tumor and normal murine tissues. The hTERT promoter was highly active in several murine tumor cell lines and a transformed cell line, but not in non-transformed and normal murine cell lines. The hTERT promoter induced tumor-specific Bax gene expression in mouse UV-2237m fibrosarcoma cells both in vitro and in vivo and suppressed syngenic tumor growth in immune-competent mice with no obvious acute or long-term toxic effects. Moreover, hTERT promoter-driven transgene expression in human CD34(+) bone marrow progenitor cells had effects similar to those observed in other normal human cells, suggesting that the hTERT promoter is much less active in CD34(+) cells than in tumor cells. Together, our data demonstrate that the hTERT promoter may allow the use of proapoptotic genes for cancer treatment without noticeable effects on progenitor cells.

Adenoviridae↗