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  • Cashin, Peter, et al. (författare)
  • Appendiceal Adenocarcinoids with Peritoneal Carcinomatosis Treated with Cytoreductive Surgery and Intraperitoneal Chemotherapy : a retrospective study of in vitro drug sensitivity and survival
  • 2011
  • Ingår i: Clinical Colorectal Cancer. - 1533-0028 .- 1938-0674. ; 10:2, s. 108-112
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The purpose of this study was to present results on cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) of appendiceal adenocarcinoid (MC) with peritoneal carcinomatosis (PC), to assess drug sensitivity of AAC, as compared with colorectal cancer (CRC), and to report any discordant histopathology. Methods: Ten patients were treated with CRS and HIPEC. Treatment, drug sensitivity profiles, histopathology, and survival data were recorded and matched with potential prognostic indicators. Drug sensitivity was assessed with short-term fluorometric microculture cytotoxicity assay and compared with peritoneal metastases from CRC. Results: Patients with completeness of cytoreduction score (CC) 1 (16.4 months). In the CC 1 group. For standard drugs, tumor cells from MC and CRC were equally sensitive; except for docetaxel, to which MC was more sensitive than CRC. Conclusion: The CC-score correlated with overall survival. Candidates for this type of treatment should be referred early for evaluation in order to reach a better CC score. Drugs used for CRC also seem adequate for treatment of MC, although other drugs, eg, docetaxel, might be more active.
  • Fryknäs, Mårten, et al. (författare)
  • Iron chelators target both proliferating and quiescent cancer cells
  • 2016
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322 .- 2045-2322. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.
  • Fryknäs, Mårten, et al. (författare)
  • Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance
  • 2013
  • Ingår i: BMC Cancer. - 1471-2407 .- 1471-2407. ; 13, s. 374-
  • 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.
  • Glimelius, Bengt, et al. (författare)
  • U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
  • 2018
  • Ingår i: ; 57:2, s. 187-194
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
  • Gullbo, J., et al. (författare)
  • Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment
  • 2011
  • Ingår i: Biochemical Pharmacology. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 82:2, s. 139-147
  • 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.
  • Al-Chalabi, Ammar, et al. (författare)
  • July 2017 ENCALS statement on edaravone
  • Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa Healthcare. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 471-474
  • Tidskriftsartikel (refereegranskat)
  • Bang, Peter, et al. (författare)
  • Free dissociable IGF-I : Association with changes in IGFBP-3 proteolysis and insulin sensitivity after surgery
  • 2016
  • Ingår i: Clinical Nutrition. - : Churchill Livingstone. - 0261-5614 .- 1532-1983. ; 35:2, s. 408-413
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Patients receiving a carbohydrate drink (CHO) before major abdominal surgery display improved insulin sensitivity postoperatively and increased proteolysis of IGFBP-3 (IGFBP-3-PA) compared to patients undergoing similar surgery after overnight fasting. Aims: We hypothesized that serum IGFBP-3-PA increases bioavailability of circulating IGF-I and preserves insulin sensitivity in patients given CHO. Design: Matched control study. Methods: At Karolinska University Hospital, patients given CHO before major elective abdominal surgery (CHO,n = 8) were compared to patients undergoing similar surgical procedures after overnight fasting (FAST,n = 10). Results from two different techniques for determination of free-dissociable IGF-I (fdIGF-I) were compared with changes in IGFBP-3-PA and insulin sensitivity. Results: Postoperatively, CHO displayed 18% improvement in insulin sensitivity (hyperinsulinemic clamp) and increased IGFBP-3-PA vs. FAST. As determined by IRMA, fdIGF-I increased by 48 +/- 25% in CHO while fdIGF-I decreased by 13 +/- 18% in FAST (p < 0.01 vs. CHO, when corrected for duration of surgery). However, fdIGF-I determined by ultra-filtration decreased similarly in both groups (-22 +/- 8% vs. -25 +/- 8%, p = 0.8) and IGFBP-1 increased similarly in both groups. Patients with less insulin resistance after surgery demonstrated larger increases in fdIGF-I by IRMA (r = 0.58, p < 0.05). Fifty-three % of the variability of the changes in fdIGF-I by IRMA could be explained by changes in IGFBP-3-PA and total IGF-I levels (p < 0.05), while IGFBP-1 did not contribute significantly. Conclusion: During conditions when serum IGF-I bioavailability is regulated by IGFBP-3 proteolysis, measurements of fdIGF-I by IRMA is of physiological relevance as it correlates with the associated changes in insulin sensitivity.
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