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  • 1
  • 2
    Keywords: THERAPY ; TOXICITY ; CYCLOPHOSPHAMIDE ; CHRONIC MYELOGENOUS LEUKEMIA ; STEM-CELL TRANSPLANTATION ; MANAGEMENT ; BCR-ABL ; IMATINIB-RESISTANT ; KINASE INHIBITOR STI571 ; SYNERGISTIC ACTIVITY
    Abstract: The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan. Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation. Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI 〈 1), additive (CI similar to 1), and predominantly antagonistic (CI 〉 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI 〈 1) at higher growth inhibition levels. Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML.
    Type of Publication: Journal article published
    PubMed ID: 25038611
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  • 3
    Abstract: PURPOSE: Artesunate (ART) has been used for a long time in the treatment of Plasmodium falciparum malaria and has been considered safe. The present phase I study aimed to determine the daily dose of ART that is well tolerated as add-on therapy in patients with breast cancer for 4 weeks of therapy. Ototoxicity could be a potential safety concern in settings different from malaria. Therefore, comprehensive audiological assessment was essential. METHODS: The ARTIC M33/2 study was a prospective, open, uncontrolled, monocentric phase I dose-escalation study to evaluate the safety and tolerability of ART in patients with advanced breast cancer. Patients received either 100, 150 or 200 mg oral ART daily for a test phase of 4 weeks as add-on therapy to their ongoing oncological treatment. For the investigation of the safety of ART for hearing, an audiological assessment was performed with each patient before the intake of ART and after 4 weeks of therapy. RESULTS: Twenty-three female patients were included in the study. During the test phase, four patients had adverse events (AEs) of the auditory system possibly related to the intake of ART. However, none of these AEs was classified as severe AE (SAE) and did not require treatment interruption. Four patients had AEs concerning the vestibular system (vertigo) during the test phase, one of which was classified as SAE. However, the SAE was fully reversible after discontinuation of ART. CONCLUSION: None of the audiological results after 4 weeks of therapy with ART showed any dose-limiting auditory toxicity. However, audiological monitoring in further clinical studies with prolonged use of oral ART in doses up to 200 mg daily is warranted. The ARTIC M33/2 study is registered at eudract.ema.europa.eu with the Number 2007-004432-23 and at clinicaltrials.gov with the Number NCT00764036.
    Type of Publication: Journal article published
    PubMed ID: 26793976
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  • 4
    Keywords: brain ; tumor ; AGENTS ; Germany ; IN-VIVO ; VIVO ; imaging ; VOLUME ; SITE ; DRUG ; TUMORS ; RELEASE ; TIME ; PATIENT ; RAT ; RATS ; CONTRAST ; CONTRAST AGENT ; MR ; MRI ; MAGNETIC-RESONANCE ; MAGNETIC-RESONANCE-SPECTROSCOPY ; magnetic resonance imaging ; prevention ; chemotherapy ; DELIVERY ; PARAMETERS ; PHARMACOKINETICS ; GD-DTPA ; MR imaging ; ELIMINATION ; RE ; LIPOSOMES ; in vivo ; EXTENT ; H1 ; BLEOMYCIN ; CYTARABINE ; fludarabine monophosphate ; fluorine MR spectroscopy ; FORMULATION ; MULTIVESICULAR LIPOSOMES
    Abstract: Introduction: Cytostatic depot preparations are interstitially administered for local chemotherapy and prevention of tumor recurrence. It would be of interest to monitor in patients as to when, to what extent, and exactly where, the drug is actually released. Liposomes containing a hydrophilic cytostatic and a hydrophilic contrast agent might be expected to release both agents simultaneously. If so, then drug release could be indirectly followed by monitoring contrast enhancement at the injection site. Methods: Multivesicular liposomes containing the antimetabolite fludarabine monophosphate and the magnetic resonance imaging (MRI) contrast agent Gd-DTPA were subcutaneously injected in rats and both agents were monitored at the injection site for 6 weeks by F-19 nuclear magnetic resonance spectroscopy (MRS) in vivo and contrast-enhanced H-1 MRI (T (1w) 3D FLASH), respectively, in a 1.5-T whole-body tomograph. The MRS and MRI data were analyzed simultaneously by pharmacokinetic modeling using NONMEM. Results: During an initial lag time, the amount of drug at the injection site stayed constant while the contrast-enhanced depot volume expanded beyond the volume injected. Drug amount and depot volume then decreased in parallel. Lag time and elimination half-life were 9 and 6 days, respectively, in three animals, and were about 50% shorter in another animal where the depot split into sub-depots. Conclusion: The preliminary data in rats suggest that simultaneous release of a hydrophilic cytostatic and a hydrophilic contrast agent from an interstitial depot can be achieved by encapsulation in liposomes. Thus, there seems to be a potential for indirect drug monitoring through imaging
    Type of Publication: Journal article published
    PubMed ID: 16506037
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  • 5
    Abstract: We investigated various combination treatment regimens employing nilotinib with established chemotherapeutic agents (daunorubicin, mitoxantrone, etoposide and cytarabine) in imatinib-sensitive and -resistant BCR-ABL-positive cells. Mitoxantrone or cytarabine showed synergism (CI 〈 1) in combination with nilotinib in imatinib-sensitive LAMA84 cells, whereas in imatinib-resistant LAMA84-R cells synergistic effects could be assessed for daunorubicin, mitoxantrone and etoposide when combined with nilotinib. In both imatinib-sensitive and -resistant K562 cells daunorubicin, mitoxantrone and etoposide demonstrated synergism in combination with nilotinib. Moreover, both daunorubicin and mitoxantrone led to synergistic antiproliferative effects when combined with nilotinib in imatinib-resistant Ba/F3 cells carrying point mutations in the ABL TK domain (E255K, E255V and T315I). Annexin V/propidium iodide staining revealed a significant enhancement of nilotinib-induced apoptosis in imatinib-resistant Ba/F3T315I and LAMA84-R cells upon combination with daunorubicin and mitoxantrone, respectively. Our results demonstrate the efficacy of combination treatment regimens employing nilotinib and established chemotherapeutic agents in improving antileukemic effects in imatinib-sensitive and imatinib-resistant cells. This may be the foundation for further study on the potential of the applied combinations in a clinical setting.
    Type of Publication: Journal article published
    PubMed ID: 19862526
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  • 6
    Keywords: ENERGIES ; BLOOD ; IN-VIVO ; MODEL ; MODELS ; imaging ; METABOLISM ; MICE ; MECHANISM ; BLOOD-FLOW ; RAT ; RATS ; tumour ; blood flow ; FLOW ; MRI ; 5-FLUOROURACIL ; MAGNETIC-RESONANCE ; MAGNETIC-RESONANCE-SPECTROSCOPY ; SPECTROSCOPY ; magnetic resonance imaging ; PLASMA ; ENERGY ; NUDE-MICE ; PHARMACOKINETICS ; RAT-TUMORS ; RIF-1 TUMORS ; MRS ; ANTICANCER DRUGS ; rodent ; OXYGENATION ; CYTOTOXICITY ; RE ; PH ; intensity ; pharmacokinetic model ; MURINE COLON-CARCINOMA ; SWITZERLAND ; LOCUS ; F-19 ; rodents ; carbogen ; GH3 PROLACTINOMAS
    Abstract: Purpose: We have shown previously that carbogen (95% 0(2), 5% CO2) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. Methods: Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy (F-19-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using P-31-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. Results: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of similar to 60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, F-19-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and P-31-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, F-19-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly (p = 0.0003) increased 5FU elimination from the tumour (i.e. decreased the t(1/2)) and significantly (p = 0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. P-31-MRS showed there were significant (pless than or equal to 0.02) increases in the hepatoma NTP/Pi ratio of 49% and transmembrane pH gradient of 0.11 units. Conclusions: We suggest that carbogen can transiently increase tumour blood flow, but this effect alone may not increase uptake of anticancer drugs without a secondary mechanism operating. In the case of the hepatoma, the increase in tumour energy status and pH gradient may be sufficient to augment 5FU metabolism to cytotoxic FNuct, while in the GH3 xenografts this was not the case. Thus carbogen breathing does not universally lead to increased uptake of anticancer drugs
    Type of Publication: Journal article published
    PubMed ID: 15592719
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  • 7
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; TOXICITY ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; FORM ; ASSAY ; CELL-DEATH ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; chemotherapy ; LIPID RAFTS ; cell lines ; N-TERMINAL KINASE ; CYTOTOXICITY ; cord blood ; multiple myeloma ; ONCOLOGY ; interaction ; erufosine ; MULTIPLE-MYELOMA CELLS ; HUMAN LEUKEMIC-CELLS ; ANTICANCER ALKYLPHOSPHOLIPIDS ; Antimigratory activity ; Haematopoietic progenitors ; SELECTIVE APOPTOSIS
    Abstract: PURPOSE: Erufosine is an i.v. injectable alkylphosphocholine which is active against various haematological malignancies in vitro. In the present study, its effects on multiple myeloma (MM) cell lines and on murine and human hematopoietic progenitor cells (HPCs) were investigated. METHODS: The following MM cell lines were used: RPMI-8226, U-266 and OPM-2. The cytotoxicity of erufosine against these cell lines was determined by the MTT-dye reduction assay. Bcl-2, Bcl-X(L) and pAkt expression levels, activation of caspases, as well as cleavage of PARP, were studied by Western blotting. Migration was evaluated by a modified Boyden-chamber assay. The haematologic toxicity of erufosine was assessed using clonogenicity assays with normal HPCs of murine or human origin. RESULTS: Significant cytotoxic activity of erufosine against the MM cell lines was found. Comparison of the characteristics of erufosine-induced cell death in the three cell lines revealed a complex mode of action with apoptotic mechanisms prevailing in OPM-2 cells and non-apoptotic mechanisms prevailing in U-266 cells. The sensitivity of the MM cell lines to erufosine-induced apoptosis correlated inversely with the Bcl-X(L) expression level. Erufosine participated in synergistic interactions with various drugs. Furthermore, it showed potent migration-inhibiting activity in RPMI-8226 cells. Erufosine was not toxic to normal HPCs of murine or human origin and even stimulated progenitors from human umbilical cord blood to form granulocyte/macrophage colonies. Moreover, erufosine ameliorated the toxicity of bendamustine to murine HPCs. CONCLUSIONS: Overall, the data presented reveal that erufosine could have potential as an antimyeloma drug and deserves further development.
    Type of Publication: Journal article published
    PubMed ID: 20177898
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  • 8
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of this study was to investigate the toxicologic responses of mice to vincristine (VCR), an established antitumor drug, and to compare them with those reported for dogs, monkeys, and humans. This comparison was expected to facilitate the continuing appraisal of the mouse as a model for toxicologic responses to antitumor drugs in human patients. In duplicate experiments, male B6D2F1 mice were treated with 1.0, 1.5, 2.0, and 3.0 mg/kg of VCR in single IP doses. These sublethal doses corresponded to 0.25, 0.40, 0.50, and 0.80 LD50. On posttreatment days 1, 3, 6, 10, 14, and 21, groups of mice were killed and blood and other tissues were collected for hematologic (8 tests), clinical chemical (15 tests), and histopathologic (11 tissues) evaluations. VCR produced dose-dependent body weight loss, reticulocytopenia, granulocytopenia, elevated plasma alkaline phosphatase, GPT, and GOT activities, and damage to the gastrointestinal epithelium. These reversible changes were most severe during the first 3 days posttreatment. The mouse was comparable to the dog and the monkey in reflecting the target organ toxicity of VCR in humans. Studies with additional antitumor drugs will be required before the overall predictive reliability of this model can be expressed quantitatively.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mice treated with lethal doses of adriamycin (A1) (IP) are rescued with a single IP dose of 3,5,5-trimethyl-2-morpholinon-3-yl radical dimer (TM3). The in vivo rescue is assumed to be analogous to the in vitro reaction of TM3 with A1 that produces the non-toxic 7-deoxy-adriamycinone (7dAone). TM3 prevents death if given within 60 min following A1 administration. Control A1-treated mice died by 8 days (median survival time) whereas TM3 rescued A1-treated mice had a median survival time of greater than 60 days.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In a phase II study, 42 patients with advanced soft-tissue sarcoma were treated with ifosfamide by 24-h infusion and mesna by 4-h IV bolus, repeated every 3 weeks. Ten patients received ifosfamide 5.0 g/m2, 20 had the dosage increased to 8.0 g/m2, and 12 received 8.0 g/m2 from the outset. Mesna was given in doses of 400 mg/m2 or 600 mg/m2. Of 40 patients evaluable for response, six (15%) achieved complete response and nine (23%) partial response. The overall response rate was 38%. The median duration of response was 11 months. Treatment was associated with falls in peripheral WBC and alopecia in all patients. Most experienced severe nausea and vomiting. In seven nephrotoxicity developed, and two of these died of renal failure. Renal tubular defects and cerebral effects also occured. Mesna largely prevented haemorrhagic cystitis. Ifosfamide offers a new alternative to previous chemotherapy for advanced soft-tissue sarcoma, but alterations in dose or method will be necessary to reduce toxicity.
    Type of Medium: Electronic Resource
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