| 1. |
- Gullbo, Joachim, et al.
(författare)
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Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.
- 2004
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Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
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Tidskriftsartikel (refereegranskat)abstract
- The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
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| 2. |
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| 3. |
- Aftab, Obaid, 1984-, et al.
(författare)
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Label free quantification of time evolving morphologies using time-lapse video microscopy enables identity control of cell lines and discovery of chemically induced differential activity in iso-genic cell line pairs
- 2015
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Ingår i: Chemometrics and Intelligent Laboratory Systems. - 0169-7439 .- 1873-3239. ; 141, s. 24-32
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Tidskriftsartikel (refereegranskat)abstract
- Label free time-lapse video microscopy based monitoring of time evolving cell population morphology has potential to offer a simple and cost effective method for identity control of cell lines. Such morphology monitoring also has potential to offer discovery of chemically induced differential changes between pairs of cell lines of interest, for example where one in a pair of cell lines is normal/sensitive and the other malignant/resistant. A new simple algorithm, pixel histogram hierarchy comparison (PHHC), for comparison of time evolving morphologies (TEM) in phase contrast time-lapse microscopy movies was applied to a set of 10 different cell lines and three different iso-genic colon cancer cell line pairs, each pair being genetically identical except for a single mutation. PHHC quantifies differences in morphology by comparing pixel histogram intensities at six different resolutions. Unsupervised clustering and machine learning based classification methods were found to accurately identify cell lines, including their respective iso-genic variants, through time-evolving morphology. Using this experimental setting, drugs with differential activity in iso-genic cell line pairs were likewise identified. Thus, this is a cost effective and expedient alternative to conventional molecular profiling techniques and might be useful as part of the quality control in research incorporating cell line models, e.g. in any cell/tumor biology or toxicology project involving drug/agent differential activity in pairs of cell line models.
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| 4. |
- Eriksson, Mathilda, et al.
(författare)
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Utilization of a right-handed coiled-coil protein from archaebacterium Staphylothermus marinus as a carrier for cisplatin
- 2009
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 29:1, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The nano-sized right-handed coiled-coil (RHCC) protein, originating from the archaebacterium Staphylothermus marinus, is stable at high salt concentrations, high temperatures, high pressures and extremes of pH. Its crystal structure reveals four hydrophobic cavities which can incorporate heavy metals. Nano-sized compounds have been used to carry cytotoxic drugs to tumours, avoiding delivery to healthy tissue, in part due to enhanced permeability in tumour blood vessels (enhanced permeability and retention effect). MATERIALS AND METHODS: The ability of RHCC to carry the platinum-containing chemotherapeutic drug cisplatin to cells, while retaining the cytotoxic potential was tested both in vitro and in vivo. RESULTS: RHCC was able to bind and enter cells in vitro and was not severely toxic or immunogenic in mice. Moreover, RHCC incorporated cisplatin, without inhibiting the cytotoxic potential of the drug against tumour cell lines in vitro or in vivo. CONCLUSION: RHCC can be used as a carrier of cisplatin without abrogating the effect of the drug.
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| 5. |
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| 6. |
- Fryknäs, Mårten, et al.
(författare)
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Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance
- 2013
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407 .- 1471-2407. ; 13, s. 374-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells. Methods: The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays. Results: One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model. Conclusions: The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance.
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| 7. |
- Hassan, Saadia Bashir, et al.
(författare)
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A hollow fiber model for in vitro studies of cytotoxic compounds : Activity of the cyanoguanidine CHS 828
- 2001
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 12:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.
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| 8. |
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| 9. |
- Hassan, Saadia Bashir, et al.
(författare)
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Alpha Terpineol : A Potential Anticancer Agent which Acts through Suppressing NF-kappa B Signalling
- 2010
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 30:6, s. 1911-1919
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alpha terpineol is a bioactive component of Salvia libanotica essential oil extract and has shown antitumour activity. Materials and Methods: The cytotoxicity of alpha terpineol towards different tumour cell lines was evaluated in vitro. Mechanistic characterization was performed using analysis of drug activity in a cell line panel and drug-induced gene expression perturbation using the connectivity map approach. Results: The small cell lung carcinoma was the cell line most sensitive to alpha terpineol. The results proposed alpha terpineol as an NF-kappa B inhibitor, which was confirmed by the observed dose-dependent inhibition of NF-kappa B translocation and activity using two NF-kappa B assays, and by the down-regulation of the expression of several NE-kappa B-related genes such as IL-1 beta and IL1R1. Conclusion: The results suggest that alpha terpineol inhibits the growth of tumour cells through a mechanism that involves inhibition of the NF-kappa B pathway.
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| 10. |
- Hassan, Saadia B., et al.
(författare)
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CHS 828 kill tumour cells by inhibiting the nuclear factor-kappa B translocation but unlikely through down-regulation of proteasome
- 2006
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:6B, s. 4431-4436
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine) has shown promising activity in many preclinical systems and in phase I/II clinical trials. The nuclear transcription factor kappa B (NF-κB) has been identified as a target for CHS 828. The aim of this study was to confirm the inhibitory effect of CHS 828 on NF-κB translocation and to explore its possible effect on the proteasome using 7 cell lines. Translocation of NF-κB from the cytoplasm to the nucleus was analysed using a quantitative cytometric system, ArrayScan®. The activity of the proteasome was assayed by monitoring the hydrolysis of a fluorogenic substrate. In parallel, the in vitro cytotoxic effect of CHS 828 was analyzed using a 72-h microtiter plate-based cytotoxicity assay (FMCA). CHS 828 inhibited NF-κB translocation in the cell lines where it was able to inhibit the tumour cell growth. However, the results did not prove any effect of CHS 828 on proteasome activity when compared to a proteasome inhibitor activity.
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