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Åleskog, Anna
Alternative names
Publications (10 of 18) Show all publications
Haglund, C., Åleskog, A., Nygren, P., Gullbo, J., Höglund, M., Wickström, M., . . . Lindhagen, E. (2012). In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues. Cancer Chemotherapy and Pharmacology, 69(3), 697-707
Open this publication in new window or tab >>In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues
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2012 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 69, no 3, p. 697-707Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The aim of this study was to evaluate a phenotypic cell panel with tumor cells from various patients and normal cells for preclinical profiles of antitumor efficacy and toxicity of anticancer drugs.

METHODS: The antitumor activity of fourteen anticancer drugs was tested in over one hundred tumor samples from patients with solid or hematological malignancies. Drug activity against four normal cell types was used for the assessment of normal tissue toxicity. In vitro activity of the drugs was compared with indications approved by the Food and Drug Administration and established adverse event profiles.

RESULTS: In general, in vitro drug activity in tumor cells from patients reflected known clinical activity of the drugs investigated. For example, the clinical activity of imatinib in chronic myeloid leukemia was clearly detected in the tumor panel. Further, and in accordance with clinical use, cisplatin and bortezomib showed high activity in ovarian cancer and myeloma samples, respectively. The normal cell models roughly reflected known clinical toxicity profiles and were able to detect differences in therapeutic index, e.g., between targeted drugs and classical cytotoxic agents. For example, the high tolerability of imatinib and the well-known renal toxicity of cisplatin were demonstrated.

CONCLUSIONS: In preclinical drug development, primary tumor cells from patients can be used for the prediction of cancer diagnosis-specific activity and may aid in the selection of diagnoses for clinical trials. By using tumor and toxicity panels together, information about therapeutic index may be derived, which may be useful when choosing among drug candidates with similar tumor effects.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-150354 (URN)10.1007/s00280-011-1746-1 (DOI)000302325600013 ()21984220 (PubMedID)
Available from: 2011-03-29 Created: 2011-03-29 Last updated: 2017-12-11Bibliographically approved
Norberg, M., Lindhagen, E., Kanduri, M., Rickardson, L., Sundström, C., Stamatopoulos, K., . . . Aleskog, A. (2012). Screening for Cytotoxic Compounds in Poor-prognostic Chronic Lymphocytic Leukemia. Anticancer Research, 32(8), 3125-3136
Open this publication in new window or tab >>Screening for Cytotoxic Compounds in Poor-prognostic Chronic Lymphocytic Leukemia
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2012 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 8, p. 3125-3136Article in journal (Refereed) Published
Abstract [en]

Background/Aim: For chronic lymphocytic leukemia (CLL) patients with poor-prognostic genomic aberrations the therapeutic options are limited. We used the Spectrum Collection library to identify compounds with anti-leukemia activity in high-risk CLL.

Materials and Methods: We identified substances with equal high cytotoxic activity in vitro in samples from poor-prognostic CLL (11q-/17p-, n=3) as compared to those from favourable-prognostic CLL (13q-, n=3). Cell survival was measured by fluorometric microculture cytotoxicity assay.

Results: Out of 2,000 compounds, 65 had a similar effect in both prognostic groups. Fifteen compounds were selected for dose-response experiments in 16 additional CLL samples. Of these compounds, 12 continued to have similar cytotoxicity between prognostic subgroups. Additional experiments demonstrated that in CLL cells with 11q or 17p deletion, 5-azacytidine induced apoptosis in a dose-dependent manner and lipoprotein lipase expression was reduced following orlistat treatment.

Conclusion: Using primary cultures of cells from high-risk CLL patients for compound screening is a feasible approach and that 5-azacytidine and orlistat exemplify substances that exhibit cytotoxicity in poor-risk CLL.

Keywords
Chronic lymphocytic leukemia, poor-risk genomic aberrations, compound library screening, cytotoxicity, 5-azacytidine, orlistat
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-181866 (URN)000306892700015 ()22843883 (PubMedID)
Available from: 2012-10-01 Created: 2012-10-01 Last updated: 2017-12-07Bibliographically approved
Kanduri, M., Tobin, G., Åleskog, A., Nilsson, K. & Rosenquist, R. (2011). The novel NF-kappa B inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia. Blood Cancer Journal, 1, e12
Open this publication in new window or tab >>The novel NF-kappa B inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia
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2011 (English)In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 1, p. e12-Article in journal (Refereed) Published
Abstract [en]

Nuclear factor-kappa B (NF-kappa B) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-kappa B inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of I kappa B alpha by IkB kinases, thus preventing NF-kappa B release. In this study, we investigated if IMD-0354 can inhibit NF-kappa B activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-kappa B were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-kappa B in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo.

Keywords
chronic lymphocytic leukemia, IMD-0354, nuclear factor-kappa B, apoptosis, drug sensitivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168436 (URN)10.1038/bcj.2011.9 (DOI)000298815400006 ()
Available from: 2012-02-10 Created: 2012-02-10 Last updated: 2017-12-07Bibliographically approved
Mansouri, M. R., Sevov, M., Åleskog, A., Jondal, M., Merup, M., Sundström, C., . . . Rosenquist, R. (2010). IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia. European Journal of Haematology, 84(2), 109-116
Open this publication in new window or tab >>IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia
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2010 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 84, no 2, p. 109-116Article in journal (Refereed) Published
Abstract [en]

T-cell leukemia/lymphoma protein 1 (TCL1) was recently shown to display an expression pattern in chronic lymphocytic leukemia (CLL) corresponding to molecular subtypes, where poor-risk patients demonstrated higher expression levels. Here, we examined the mRNA expression pattern of TCL1 in 144 patients with CLL, including 67 immunoglobulin heavy-chain variable (IGHV) mutated, 58 IGHV unmutated and 19 patients with IGHV3-21 usage. A higher TCL1 expression level was detected in patients with CLL with unmutated vs. mutated IGHV genes (P < 0.001), whereas no difference was demonstrated within the IGHV3-21 cohort (i.e., mutated vs. unmutated and stereotyped vs. non-stereotyped complementarity determining region 3). The IGHV3-21 subgroup displayed high TCL1 mRNA expression, differing significantly from other IGHV mutated cases (P < 0.001), although 11/19 had mutated IGHV genes. Furthermore, high TCL1 expression levels were associated with significantly shorter overall survival (P < 0.001). Altogether, we show that TCL1 mRNA expression may predict clinical outcome in CLL and that the IGHV3-21 subset, regardless of mutational status, displays high TCL1 expression.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-121110 (URN)10.1111/j.1600-0609.2009.01369.x (DOI)000273301600003 ()19889012 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2019-04-01
Lindhagen, E., Rickardson, L., Elliott, G., Leoni, L., Nygren, P., Larsson, R. & Åleskog, A. (2007). Pharmacological profiling of novel non-COX-inhibiting indole-pyran analogues of etodolac reveals high solid tumour activity of SDX-308 in vitro. Investigational new drugs, 25(4), 297-303
Open this publication in new window or tab >>Pharmacological profiling of novel non-COX-inhibiting indole-pyran analogues of etodolac reveals high solid tumour activity of SDX-308 in vitro
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2007 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 25, no 4, p. 297-303Article in journal (Refereed) Published
Abstract [en]

SDX-308 and SDX-309 are potent indole-pyran analogues of SDX-101 (R-etodolac) which has anti-tumour activity unrelated to cyclooxygenase-2 inhibition. Their cytotoxic activity was further studied herein using a well-characterized human tumour cell-line panel containing ten cell lines, as well as in 58 primary tumour cell samples from a variety of diagnoses. The indole-pyran analogues of SDX-101 were in general considerably more active in both cancer cell lines and primary tumour samples. Low cross-reactivity with standard agents was observed, indicating a unique mechanism of action. No apparent influence on efficacy was observed via classical mechanisms of multidrug-resistance. SDX-101 and SDX-309 showed higher relative activity in haematological compared to solid tumour samples, while SDX-308 had pronounced solid-tumour activity. High SDX-308 cytotoxic efficacy was observed in non-small cell lung cancer, renal cancer and ovarian cancer samples, and also in chronic lymphocytic leukaemia. In conclusion, the indole-pyran analogues showed a favourable pharmacological profile and represent a potentially important new class of drugs for cancer treatment.

Keywords
Antineoplastic Agents/*pharmacology, Cell Line; Tumor, Drug Screening Assays; Antitumor, Etodolac/*analogs & derivatives/*pharmacology, Female, Heterocyclic Compounds; 3-Ring/*pharmacology, Humans
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-15630 (URN)10.1007/s10637-007-9049-4 (DOI)000247275600002 ()17440681 (PubMedID)
Available from: 2008-02-26 Created: 2008-02-26 Last updated: 2017-12-08Bibliographically approved
Hassan, S. B., Haglund, C., Åleskog, A., Larsson, R. & Lindhagen, E. (2007). Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity. Toxicology in Vitro, 21(6), 1174-1181
Open this publication in new window or tab >>Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity
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2007 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 21, no 6, p. 1174-1181Article in journal (Refereed) Published
Abstract [en]

Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50–300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.

Keywords
Animals, Antineoplastic Agents/*toxicity, Cell Survival/drug effects, Cells; Cultured, Dogs, Female, Fluorometry, Humans, Leukocytes; Mononuclear/*drug effects, Male, Mice, Mice; Inbred BALB C, Rats, Rats; Inbred Strains, Species Specificity, Toxicity Tests/methods
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-15582 (URN)10.1016/j.tiv.2007.03.009 (DOI)000249542300022 ()17481850 (PubMedID)
Available from: 2008-02-21 Created: 2008-02-21 Last updated: 2017-12-08Bibliographically approved
Lindhagen, E., Nissle, S., Leoni, L., Elliott, G., Chao, Q., Larsson, R. & Åleskog, A. (2007). R-etodolac (SDX-101) and the related indole-pyran analogues SDX-308 and SDX-309 potentiate the antileukemic activity of standard cytotoxic agents in primary chronic lymphocytic leukaemia cells. Cancer Chemotherapy and Pharmacology, 60(4), 545-553
Open this publication in new window or tab >>R-etodolac (SDX-101) and the related indole-pyran analogues SDX-308 and SDX-309 potentiate the antileukemic activity of standard cytotoxic agents in primary chronic lymphocytic leukaemia cells
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2007 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 60, no 4, p. 545-553Article in journal (Refereed) Published
Abstract [en]

Objective: SDX-101 is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac, and has anti-tumour activity in chronic lymphocytic leukaemia (CLL). SDX-308 and SDX-309 are more potent, structurally related indole-pyran analogues of SDX-101. The current study was performed to investigate and quantify the cytotoxic potentiating effects resulting from a combination of either SDX-101, SDX-308 or SDX-309 with standard cytotoxic agents used in the CLL treatment today. Methods: The lymphoma cell line U937-gtb was used, together with primary tumour cells isolated from seven CLL patients. Combinations between chlorambucil and each one of the agents etodolac, SDX-101, SDX-308 and SDX-309 were studied. In addition, SDX-309 was combined with fludarabine, doxorubicin or vincristine. Both simultaneous and sequential exposures were explored using the median-effect method. Results: Most combinations were additive, which could be of clinical benefit since SDX-101 has been shown to be well tolerated. At the 70% effect level, synergy was observed between SDX-308 and chlorambucil in U937-gtb cells and in two-third of the CLL samples. Since chlorambucil is the most important drug in CLL therapy today and SDX-308 is presently targeted as the lead clinical candidate, this combination would be interesting for further studies. Vincristine and SDX-309 were synergistic in two-fourth of CLL samples. Conclusions: To conclude, the non-COX-inhibiting etodolac-derivatives SDX-101, SDX-308 and SDX-309 are potential candidates for combination treatment of CLL. Especially, SDX-308 in combination with chlorambucil warrants further evaluation.

Keywords
CalcuSyn, Combination, Etodolac, SDX-101, SDX-308
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-24876 (URN)10.1007/s00280-006-0400-9 (DOI)000248134700010 ()17186240 (PubMedID)
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2018-01-12Bibliographically approved
Skogsberg, S., Tobin, G., Kröber, A., Kienle, D., Thunberg, U., Åleskog, A., . . . Rosenquist, R. (2006). The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia.. Leukemia, 20(1), 77-81
Open this publication in new window or tab >>The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia.
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2006 (English)In: Leukemia, ISSN 0887-6924, Vol. 20, no 1, p. 77-81Article in journal (Refereed) Published
Keywords
Adult, Aged, Aged; 80 and over, Cohort Studies, Cytogenetic Analysis, Female, Humans, Leukemia; Lymphocytic; Chronic/diagnosis/*genetics, Male, Middle Aged, Polymorphism; Genetic/*genetics, Prognosis, Promoter Regions (Genetics), Retrospective Studies, Survival Rate, Tumor Markers; Biological/biosynthesis/*genetics, bcl-2-Associated X Protein/biosynthesis/*genetics
Identifiers
urn:nbn:se:uu:diva-24890 (URN)16307023 (PubMedID)
Available from: 2008-05-21 Created: 2008-05-21 Last updated: 2011-01-11
Hallböök, H., Barbany, G., Åleskog, A., Björnberg, A., Larsson, R., Sundström, C. & Lindhagen, E. (2005). In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia. Anti-Cancer Drugs, 16(6), 631-634
Open this publication in new window or tab >>In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia
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2005 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 16, no 6, p. 631-634Article in journal (Refereed) Published
Abstract [en]

We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92962 (URN)15930891 (PubMedID)
Available from: 2005-04-27 Created: 2005-04-27 Last updated: 2017-12-14Bibliographically approved
Åleskog, A., Höglund, M., Pettersson, J., Hermansson, M., Larsson, R. & Lindhagen, E. (2005). In vitro activity of the flt3-inhibitor su5614 and standard cytotoxic agents in tumour cells from patients with wild type and mutated flt3 acute myeloid leukaemia.. Leuk Res, 29(9), 1079-81
Open this publication in new window or tab >>In vitro activity of the flt3-inhibitor su5614 and standard cytotoxic agents in tumour cells from patients with wild type and mutated flt3 acute myeloid leukaemia.
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2005 (English)In: Leuk Res, ISSN 0145-2126, Vol. 29, no 9, p. 1079-81Article in journal (Refereed) Published
Keywords
Acute Disease, Antineoplastic Agents/*administration & dosage, Humans, Indoles/administration & dosage/*pharmacology, Leukemia; Myeloid/*drug therapy/pathology, Point Mutation, Polymerase Chain Reaction, Proto-Oncogene Proteins/*antagonists & inhibitors/genetics, Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/genetics, Research Support; Non-U.S. Gov't, Tumor Cells; Cultured, fms-Like Tyrosine Kinase 3
Identifiers
urn:nbn:se:uu:diva-80416 (URN)16038735 (PubMedID)
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2011-01-11
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