| 21. |
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| 22. |
- 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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| 23. |
- Godskesen, Tove, et al.
(författare)
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Phase 1 clinical trials in end-stage cancer : patient understanding of trial premises and motives for participation
- 2013
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Ingår i: Supportive Care in Cancer. - : Springer Science and Business Media LLC. - 0941-4355 .- 1433-7339. ; 21:11, s. 3137-3142
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In cancer, phase 1 clinical trials on new drugs mostly involve patients with advanced disease that is unresponsive to standard therapy. The purpose of this study was to explore the difficult ethical problems related to patient information and motives for participation in such trials.METHOD: A descriptive and explorative qualitative design was used. Fourteen cancer patients from three different phase 1 trials in end-stage cancer were interviewed. The interviews were analysed using qualitative content analysis.RESULTS: The patients expressed unrealistic expectations of therapeutic benefit and inadequate understanding of the trials' purpose, so-called therapeutic misconception. However, they reported a positive attitude towards participation. Thus, the patients valued the close and unique medical and psychological attention they received by participating. Participation also made them feel unique and notable.CONCLUSIONS: Patients with end-stage cancer participating in phase 1 clinical trials are unaware of the very small potential for treatment benefit and the risk of harm. Trial participation may offer hope and social-emotional support and a strategy for coping with the emotional stress associated with advanced cancer and may, consequently, improve emotional well-being.
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| 24. |
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| 25. |
- Gullbo, Joachim, et al.
(författare)
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Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment
- 2011
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 82:2, s. 139-147
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Tidskriftsartikel (refereegranskat)abstract
- Primary cultures of patient tumor cells (PCPTC) have been used for prediction of diagnosis-specific activity and individual patient response to anticancer drugs, but have not been utilized as a model for identification of novel drugs in high throughput screening. In the present study, ovarian carcinoma cells from three patients were tested in response to a library of 3000 chemically diverse compounds. Eight hits were retrieved after counter screening using normal epithelial cells, and one of the two structurally related hit compounds was selected for further preclinical evaluation. This compound, designated VLX 50, demonstrated a broad spectrum of activity when tested in a panel of PCPTCs representing different forms of leukemia and solid tumors and displayed a high tumor to normal cell activity. VLX 50 induced delayed cell death with some features of classical apoptosis. Significant in vivo activity was confirmed on primary cultures of human ovarian carcinoma cells in mice using the hollow fiber model. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. This query signature was analyzed using the Gene Set Enrichment Analysis and the Connectivity Map database. Strong connections to hypoxia inducible factor 1 and iron chelators were retrieved. The mechanistic hypothesis of intracellular iron depletion leading to hypoxia signaling was confirmed by a series of experiments. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy.
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| 26. |
- Haglund, Caroline, et al.
(författare)
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In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues
- 2012
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 69:3, s. 697-707
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 27. |
- Hansson, Johan, 1964-, et al.
(författare)
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Quality of life in peritoneal carcinomatosis after cytoreductive surgery and intraperitoneal chemotherapy
- 2012
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Tidskriftsartikel (refereegranskat)abstract
- Background:Cytoreductive surgery (CRS) plus intraperitoneal chemotherapy (IPC) is considered the most optimal treatment for peritoneal carcinomatosis (PC). Health-related quality of life (HRQL) after treatment is largely unknown. The aims were to assess HRQL in patients with PC treated with CRS and IPC and to analyse the influence of clinical variables on HRQL.Methods:HRQL was assessed prospectively between November 2001 and March 2005 in 64 consecutive patients with PC through two different self-administered instruments, EORTC QLQ-C30 v3.0 (QLQ-C30) and the SF-36 Health Survey (SF-36), preoperatively, and after 3 and 8 months. Results:For QLQ-C30, 44 (69%) and for SF-36, 42 (66%) out of 64 patients had a complete follow-up. Most scales were worsened at baseline compared to reference in both instruments. HRQL was reduced at 3-months in QLQ-C30 (physical, role and emotional functioning) and in SF-36 (physical summary score). At 8-months, all scales returned to baseline in QLQ-C30, except physical functioning which was still reduced and dyspnoea that was worsened. In SF-36, all values returned to baseline levels. At 8-months, presence of a stoma worsened social functioning and a high peritoneal cancer index decreased social functioning and global QoL, the use of hyperthermic intraperitoneal chemotherapy and 30-days postoperative morbidity had no impact on HRQL. Conclusion: CRS with IPC results in reasonable short-term HRQL despite high initial morbidity and an initial decrease in HRQL parameters. The study adds to the notion that this treatment appears beneficial in light of probable life prolongation, despite considerable toxicity.
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| 28. |
- Hassan, Saadia Bashir, et al.
(författare)
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The Nanoparticulate Quillaja Saponin BBE Is Selectively Active Towards Renal Cell Carcinoma
- 2013
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 33:1, s. 143-151
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To characterize the cytotoxic effect of BBE, the particulate of desacyl-saponin, in model systems of solid tumours. Materials and Methods: Cytotoxic activity of BBE was investigated in solid human tumour cell lines, in tumour cells from patients with renal cell carcinoma, in normal human renal cells and in peripheral blood mononuclear cells. The BBE mode of cell death was assessed in vitro. In vivo effect of BBE was evaluated in xenograft-bearing mice. Results: BBE was selectively active against renal cell carcinoma, with no or little effect on normal cells. BBE induced caspase activity and apoptosis. An inhibitory activity of BBE on xenograft tumour growth, with no apparent signs of haematological toxicity was shown. In the non-proliferative model of patient tumour cells, BBE was active on only 1/5 patient samples, suggesting association of BBE effect with cell proliferation. Conclusion: BBE has interesting activities against renal cell carcinoma and should be further explored as a drug against this resistant tumour type.
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| 29. |
- Hassan, Saadia, et al.
(författare)
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Novel activity of acriflavine against colorectal cancer tumor cells
- 2011
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Ingår i: Cancer Science. - : Wiley. - 1347-9032 .- 1349-7006. ; 102:12, s. 2206-2213
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Tidskriftsartikel (refereegranskat)abstract
- A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.
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| 30. |
- Hu, Kefei, et al.
(författare)
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Nanoparticulate Quillaja saponin induces apoptosis in human leukemia cell lines with a high therapeutic index
- 2010
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Ingår i: International Journal of Nanomedicine. - 1176-9114 .- 1178-2013. ; 5:1, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol. Two fractions of QS were selected for particle formation, one with an acyl-chain (ASAP) was used to form killing and growth-inhibiting (KGI) particles, and the other without the acyl-chain (DSAP) was used to formulate blocking and balancing effect (BBE) particles. KGI showed significant growth inhibiting and cancer cell-killing activities in nine of 10 cell lines while BBE showed that on one cell line. The monoblastoid lymphoma cell line U937 was selected for analyzing the mode of action. Low concentrations of KGI (0.5 and 2 microg/mL) induced irreversible exit from the cell cycle, differentiation measured by cytokine production, and eventually programmed cell death (apoptosis). Compared to normal human monocytes, the U937 cells were 30-fold more sensitive to KGI. The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner. In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.
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