Publikationsserver der Universitätsbibliothek Marburg

Titel:Überprüfung des Drug Delivery Konzepts von „Lipid-Nucleosid- und Polysaccharid-Konjugaten von 5-Fluorouracil“
Autor:Farhat, Anisa
Weitere Beteiligte: Kinscherf, Ralf (Prof. Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0544
URN: urn:nbn:de:hebis:04-z2016-05447
DOI: https://doi.org/10.17192/z2016.0544
DDC: Medizin
Titel (trans.):Verification of drug delivery concept of "lipid - nucleoside and polysaccharide conjugates of 5-fluorouracil"
Publikationsdatum:2016-07-26
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
5-Fluorouracil, 5-fluorouracil

Zusammenfassung:
2012 standen maligne Erkrankungen an zweiter Stelle der Todesursachenstatistik in Deutschland (Becker & Holzmeier 2012). Einen wichtigen Baustein in der Therapie der malignen Erkrankungen stellt die Chemotherapie dar. Trotz großer Fortschritte in den vergangenen Jahren konnte nur eine geringe Verbesserung des Überlebens der Patienten erzielt werden (Bourret et al. 1979, Krook et al. 1991). Das Uracil-Analogon 5-Fluorouracil (5-FU) ist ein Antimetabolit, der weit verbreitet in der Chemotherapie maligner Tumoren Anwendung findet (Bodner-Adler et al. 2007, Carrato 2008, Khosravi Shahi et al. 2007, Kish et al. 1994, Zhao et al. 2013). Eines der größten Handicaps von Chemotherapeutika, wie 5-FU, ist die insuffiziente Penetration der Zellmembran, die durch eine hohe Hydrophilie bedingt ist (Malecki et al. 2013a). Daher haben Prof. Dr. Rosemeyer und Frau Dr. Malecki im Rahmen eines Kooperationsprojekts (Prof. Rosemeyer, Osnabrück/Prof. Kinscherf, Marburg) verschiedene Derivate von 5-Fluorouridine (5-FUrd, 2a) entwickelt, welche lipophile Reste in N(3)- und/oder in 2‘3‘-O-Position tragen (3a-7a, 3c, 2c, 3b-7b), mit dem Ziel durch erhöhte Lipophilie der Derivate eine verbesserte Penetration und eine geringere Rate an Nebenwirkungen zu erreichen (Köstler et al 2013, Malecki et al. 2013a, Malecki et al. 2013b, Malecki et al. 2014, Malecki & Rosemeyer 2010, Rosemeyer et al. 2012, Rosemeyer & Malecki 2012, Werz et al. 2013). Zusätzlich wurde zum Vergleich das 2‘3‘-O-Nonadecylidene Derivat von Uridin, 3c, hergestellt (Köstler et al. 2013). In dieser Dissertation erfolgte die in vitro-Testung des Drug Delivery Konzeptes der „Lipid-Nucleosid- und Polysaccharid-Konjugate von 5-FU (2a, 3a-7a, 3c, 2c, 3b-7b)“ an den Krebszelllinien HT-29 (humanes Kolonkarzinom), HepG2 (humanes hepatozelluläres Karzinom), sowie RENCA (murine Nierenzellkarzinom) und an Zellen des Immunsystems, d.h. differenzierten, humanen Makrophagen (THP-1). Um die Frage zu klären, ob die Substanzen die Zellmembran passieren können, und in welchem Zellkompartiment sie danach lokalisiert sind, wurden HT-29-Zellen mit ATTO 245®-konjugierten Test-Substanzen (2c, 3b-7b) für 24 h inkubiert. Alle Derivate passierten die Zellmembran und akkumulierten im Zytoplasma, unter Aussparung des Zellkerns. Nur das Derivat 2c zeigte eine granulierte Verteilung im Zytoplasma. Ein Schwerpunkt dieser Dissertation war es, den Einfluss der Aufnahme der Testsubstanzen (3a-7a, 3c) auf die Proliferation und Apoptose der Zellen und die zytostatische/zytotoxische Aktivität der Derivate im Vergleich zu 5-FU (1) und 5-FUrd (2a) zu untersuchen. Nach 24 h, 48 h bzw. 72 h Inkubation der humanen Kolonkarzinomzellinie HT-29 mit den Derivaten 1 (5-FU) (14-23%, 35-46%, bzw. 30-58%) und 2a (5-FUrd) (33-45%, 60-67%, bzw. 58-67%) konnte im Vergleich zur Negativkontrolle eine signifikante Reduktion der Viabilität der Zellen beobachtet werden. Nach 24 h Inkubation der HT-29-Zellen zeigten in den Konzentrationen 40 µM und 80 µM die Derivate 3a (77% und 95%), 5a (30% und 86%) und 3c (89% und 96%) eine signifikante Abnahme der Viabilität im Vergleich zur Negativkontrolle. Diese drei Derivate zeigten nach 24 h Inkubation in den Konzentrationen 40 µM und 80 µM ebenfalls im Vergleich zur Positivkontrolle (1) eine signifikante Abnahme der Viabilität der HT-29-Zellen (61-81%, 73% bzw. 80-82%). Nach 48 h Inkubation der HT-29-Zellen mit den Derivaten konnte bei vier Derivaten in den Konzentrationen 40 µM und 80 µM eine signifikante Abnahme der Viabilität im Vergleich zu 5-FU (~Positivkontrolle) beobachtet werden: 3a (9-54%), 5a (5-48%), 7a (2-30%) und 3c (53-63%). Die Derivate 4a und 6a zeigten keinen Effekt auf die Viabilität der HT-29-Zellen. Die Derivate 3a, 5a, 7a und 3c zeigten auch bei anderen Krebszelllinien (RENCA und HepG2) eine signifikante Abnahme der Viabilität: Nach 48 h Inkubation der RENCA-Zelllinie mit den Derivaten, zeigten die Derivate 3a (51-57%) und 5a (56%) eine signifikante Abnahme der Viabilität im Vergleich zu 5-FU. Die Derivate 3c (38-49%) und 7a (25-44%) wiesen bei RENCA-Zellen ähnliche zytostatische Effekte auf, wie die Substanzen 1 (29-48%) und 2a (41-46%). Nach 48 h Inkubation der HepG2-Zelllinie mit den Derivaten konnte bei den Derivaten 3a (72-75%),5a (53%), 7a (43%) und 3c (22-74%) eine signifikante Abnahme der Viabilität im Vergleich zu 5-FU beobachtet werden. Von besonderem Interesse war das Ergebnis der Testung der Derivate an differenzierten THP-1-Makrophagen, um zwischen zytotoxischen Effekten und Nebenwirkungen unterscheiden zu können. Das Derivat 5a zeigte nach 48 h Inkubation eine signifikant um 6-27% erhöhte Zunahme der Viabilität im Vergleich zu 5-FU (~Positivkontrolle). Die mit ATTO 425®-konjugierten 5-Fluorouridinderivate 3b, 4b, 5b, 6b und 7b wurden bzgl. ihrer Effekte auf die Viabilität der HT-29-Kolonkarzinomzellen getestet, nach 24 h und nach 48 h Inkubationszeit. Die mit ATTO 425®-konjugierten 5-FUrd Derivate zeigten in allen getesteten Konzentrationen (10-80 µM) im Vergleich zur Kontrolle keine Unterschiede bzgl. Viabilität der Zellen. Nur das mit ATTO 425®-konjugierte 5-FUrd (2c) zeigte in den Konzentrationen 10-80 µM im Vergleich zur Kontrolle eine signifikante Abnahme der Viabilität der HT-29-Zellen um 31-52% bzw. 41-57%. Zusätzlich testeten wir den Einfluss der Derivate auf die Induktion der Apoptose und Proliferation im Vergleich zu 5-FU (1) und 5-FUrd (2a) bei HT-29-Zellen nach 1 h, 2 h, 4 h und 6 h Inkubationszeit. Das Derivat 5a zeigte signifikante Zunahmen der Apoptose bei 80 µM nach 2 h Inkubationszeit (um das 3,1-Fache), nach 4 h (um das 3-Fache) bzw. 6 h (um das 4-Fache). Nach 6 h Inkubation konnte bei 5a auch bei 40 µM eine signifikante Zunahme der Apoptose um das 3,3-Fache beobachtet werden. Des Weiteren wurde die Gensignatur (zur Testung der Signaltransduktion) der HT-29-Zellen nach Behandlung mit diesen Substanzen untersucht. In der Real-time PCR (qRT-PCR) zeigte das Derivat 5a bei 40 µM eine signifikante Zunahme der Expression des Tumorsuppressorgens p53 um das 2-Fache im Vergleich zur Negativ- und Positivkontrolle (5-FU), sowie eine 1,8-fache Zunahme der Expression des proapoptotischen Caspase 3 Gens. In dieser Arbeit konnte gezeigt werden, dass bei mehreren Krebszelllinien einige Derivate von 5-FUrd (2a) effektiver in ihrer Zytotoxizität sind, als 5-FU (1) oder 5-FUrd (2a). Besonders das Derivat 5a ist von großem Interesse, da es trotz der hohen zytotoxischen Aktivität bei Krebszelllinien, keine zytotoxischen Effekte bei differenzierten Makrophagen (~Immunzellen) zeigt. Das Derivat 5a könnte somit ein neuartiges, zytotoxisches, multipotentes Chemotherapeutikum darstellen. Zur abschließenden Beurteilung des pharmakologischen/therapeutischen Potentials sind allerdings weitere Untersuchungen, z. B. an Mikrotumoren/-sphären, sowie tierexperimentelle und prospektive klinische Studien notwendig.

Bibliographie / References

  1. Kufe DW, Major PP. 1981. 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. The Journal of biological chemistry 256 (19):9802- 05
  2. Nita ME, Nagawa H, Tominaga O, Tsuno N, Fujii S, et al. 1998. 5-Fluorouracil induces apoptosis in human Kolon cancer cell lines with modulation of Bcl-2 family proteins. British journal of cancer 78 (8):986-92
  3. Longley DB, Harkin DP, Johnston PG. 2003. 5-fluorouracil: mechanisms of action and clinical strategies. Nature reviews. Cancer 3 (5):330-38
  4. Cheng M, He B, Wan T, Zhu W, Han J, et al. 2012. 5-Fluorouracil nanoparticles inhibit hepatocellular carcinoma via activation of the p53 pathway in the orthotopic transplant mouse model. PloS one 7 (10):e47115
  5. Doong SL, Dolnick BJ. 1988. 5-Fluorouracil substitution alters pre-mRNA splicing in vitro. The Journal of biological chemistry 263 (9):4467-73
  6. Bustin SA. 2000. Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. Journal of molecular endocrinology 25 (2):169- 93
  7. Kodama Y, Fumoto S, Nishi J, Nakashima M, Sasaki H, Nakamura J, Nishida K. 2008. Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects. Biological & pharmaceutical bulletin 31 (5):1049-52
  8. Barone C. 2008. Adjuvant chemotherapy of Kolon cancer current strategies. European Journal of Cancer Supplements 6 (14):60-63
  9. Lombardi L, Morelli F, Cinieri S, Santini D, Silvestris N, et al. 2010. Adjuvant Kolon cancer chemotherapy: where we are and where we'll go. Cancer treatment reviews 36 Suppl 3:S34-41
  10. Carrato A. 2008. Adjuvant treatment of colorectal cancer. Gastrointestinal cancer research : GCR 2 (4 Suppl):S42-6
  11. Bull S, Langezaal I, Clothier R, Coecke S. 2001. A Genetically engineered cell-based system for detecting metabolism-mediated toxicity. Alternatives to laboratory animals : ATLA 29 (6):703-16
  12. Moskal A, Norat T, Ferrari P, Riboli E. 2007. Alcohol intake and colorectal cancer risk: a dose-response meta-analysis of published cohort studies. International journal of cancer. Journal international du cancer 120 (3):664-71
  13. Spirio LN, Samowitz W, Robertson J, Robertson M, Burt RW, Leppert M, White R. 1998. Alleles of APC modulate the frequency and classes of mutations that lead to Kolon polyps. Nature genetics 20 (4):385-88
  14. Benson AB, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, et al. 2004. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II Kolon cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22 (16):3408-19
  15. Arndt-Jovin DJ, Jovin TM. 1977. Analysis and sorting of living cells according to deoxyribonucleic acid content. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 25 (7):585-89
  16. Joppien S, Maier S, Wendling D. 2011. Anlehnung an: Basics experimentelle Doktorarbeit. S. 59. München: Elsevier, Urban u. Fischer. 1. Aufl
  17. Stewart SL, Wike JM, Kato I, Lewis DR, Michaud F. 2006. A population-based study of colorectal cancer histology in the United States, 1998-2001. Cancer 107 (5 Suppl):1128-41
  18. Johns LE, Houlston RS. 2001. A systematic review and meta-analysis of familial colorectal cancer risk. The American journal of gastroenterology 96 (10):2992-3003
  19. Isbert C, Germer C. 2012. Bedeutung der Endoskopie und Endosonographie für das lokale Staging beim Rektumkarzinom. Der Chirurg; Zeitschrift für alle Gebiete der operativen Medizen 83 (5):430-38
  20. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, et al. 2008. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26 (12):2013-19
  21. Ishii T, Marumo K. 2004. Biochemical modulation of 5-fluorouracil with interferon alpha/beta and gamma on murine renal cell carcinoma. International journal of urology : official journal of the Japanese Urological Association 11 (11):993-1000
  22. Bodner-Adler B, Bodner K, Zeisler H. 2007. Breast cancer diagnosed during pregnancy. Anticancer research 27 (3B):1705-07
  23. Coleman MP, Quaresma M, Berrino F, Lutz J, Angelis R de, et al. 2008. Cancer survival in five continents: a worldwide population-based study (CONCORD). The Lancet. Oncology 9 (8):730-56
  24. Johnston PG, Kaye S. 2001. Capecitabine: a novel agent for the treatment of solid tumors. Anti-cancer drugs 12 (8):639-46
  25. Haller DG, Tabernero J, Maroun J, Braud F de, Price T, et al. 2011. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III Kolon cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29 (11):1465-71
  26. Kurokawa M, Kornbluth S. 2009. Caspases and kinases in a death grip. Cell 138 (5):838-54
  27. Santi DV, Hardy LW. 1987. Catalytic mechanism and inhibition of tRNA (uracil-5- )methyltransferase: evidence for covalent catalysis. Biochemistry 26 (26):8599-606
  28. Hofheinz R, Wenz F, Post S, Matzdorff A, Laechelt S, et al. 2012. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. The Lancet. Oncology 13 (6):579-88
  29. Diasio RB, Harris BE. 1989. Clinical pharmacology of 5-fluorouracil. Clinical pharmacokinetics 16 (4):215-37
  30. Mekenkamp, L J M, Koopman M, Teerenstra S, van Krieken, J H J M, Mol L, Nagtegaal ID, Punt, C J A. 2010. Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases. British journal of cancer 103 (2):159-64
  31. Speights VO, Johnson MW, Stoltenberg PH, Rappaport ES, Helbert B, Riggs M. 1991. Colorectal cancer: current trends in initial clinical manifestations. Southern medical journal 84 (5):575-78
  32. Neri E, Giusti P, Battolla L, Vagli P, Boraschi P, et al. 2002. Colorectal cancer: role of CT Kolonography in preoperative evaluation after incomplete Kolonoscopy. Radiology 223 (3):615-19
  33. Nordlinger B, van Cutsem E, Gruenberger T, Glimelius B, Poston G, et al. 2009. Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 20 (6):985-92
  34. Hamid R, Rotshteyn Y, Rabadi L, Parikh R, Bullock P. 2004. Comparison of alamar blue and MTT assays for high through-put screening. Toxicology in vitro: an international journal published in association with BIBRA 18 (5):703-10
  35. Miret S, De Groene, Els M, Klaffke W. 2006. Comparison of in vitro assays of cellular toxicity in the human hepatic cell line HepG2. Journal of biomolecular screening 11 (2):184-93
  36. Boncler M, Różalski M, Krajewska U, Podsędek A, Watala C. 2014. Comparison of PrestoBlue and MTT assays of cellular viability in the assessment of antiproliferative effects of plant extracts on human endothelial cells. Journal of pharmacological and toxicological methods 69 (1):9-16
  37. Soni SD, Srikrishnan T. 2004. Crystal structure and conformation of 5-fluorouridine: conformational preferences for 5-fluorinated pyranosides. Nucleosides, nucleotides & nucleic acids 23 (11):1779-95
  38. Bourret LA, Goetinck PF, Hintz R, Rodan GA. 1979. Cyclic 3' ,5'-AMP changes in chondrocytes of the proteoglycan-deficient chick embryonic mutant, nanomelia. FEBS letters 108 (2):353-55
  39. Eda H, Fujimoto K, Watanabe S, Ura M, Hino A, et al. 1993. Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5'-deoxy-5-fluorouridine. Cancer chemotherapy and pharmacology 32 (5):333-38
  40. Weinreich J, Schott TC, Königsrainer I, Küper M, Königsrainer A, Schott H. 2012. Cytostatic activity of a 5-fluoro-2'-deoxyuridine-alendronate conjugate against gastric adenocarcinoma and non-malignant intestinal and fibroblast cell lines. Anticancer research 32 (10):4299-305
  41. Weinreich J, Schott S, Königsrainer I, Zieker D, Königsrainer A, Schott H. 2011. Cytostatic activity of the duplex drug linking 2'-deoxy-5-fluorouridine (5FdU) with 3'- C-ethynylcytidine (ECyd) against gastric adenocarcinoma cell lines. Investigational new drugs 29 (6):1294-302
  42. Farhat A, Malecki E, Bonaterra GA, Röthlein D, Wolf M, et al. 2014. Cytostatic/cytotoxic effects of 5-fluorouridine nucleolipids on Kolon, hepatocellular, and renal carcinoma cells: in vitro identification of a potential cytotoxic multi-anticancer drug. Chemistry & biodiversity 11 (3):469-82
  43. Becker N, Holzmeier S. Die häufigsten Todesursachengruppen in Deutschland 2012. Abteilung Epidemiologie von Krebserkrankungen, Deutsches Krebsforschungszentrum Heidelberg
  44. Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, et al. 1999. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. The Journal of clinical investigation 104 (3):263-69
  45. Rutkowski A, Bujko K, Nowacki MP, Chmielik E, Nasierowska-Guttmejer A, Wojnar A. 2008. Distal bowel surgical margin shorter than 1 cm after preoperative radiation for rectal cancer: is it safe? Annals of surgical oncology 15 (11):3124-31
  46. Chung DC, Rustgi AK. 1995. DNA mismatch repair and cancer. Gastroenterology 109 (5):1685-99
  47. Becker N, Holzmeier S. Durchschnittliche Fallzahlen und altersspez. Mortalitätsraten pro 100 000 nach Altersgruppen 2010-2012 (ICD 153, 154). Abteilung Epidemiologie von Krebserkrankungen. In Sabine Holzmeier Abteilung Epidemiologie von Krebserkrankungen Deutsches Krebsforschungszentrum Heidelberg
  48. Moiel D, Thompson J. 2011. Early detection of Kolon cancer-the kaiser permanente northwest 30-year history: how do we measure success? Is it the test, the number of tests, the stage, or the percentage of screen-detected patients? The Permanente journal 15 (4):30-38
  49. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, et al. 1991. Effective surgical adjuvant therapy for high-risk rectal carcinoma. The New England journal of medicine 324 (11):709-15
  50. Barillari P, Ramacciato G, Angelis R de, Gozzo P, Indinnimeo M, et al. 1990. Effect of preoperative Kolonoscopy on the incidence of synchronous and metachronous neoplasms. Acta chirurgica Scandinavica 156 (2):163-66
  51. Kahi CJ, Imperiale TF, Juliar BE, Rex DK. 2009. Effect of screening Kolonoscopy on colorectal cancer incidence and mortality. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 7 (7):770-5; quiz 711
  52. Grogan BC, Parker JB, Guminski AF, Stivers JT. 2011. Effect of the thymidylate synthase inhibitors on dUTP and TTP pool levels and the activities of DNA repair glycosylases on uracil and 5-fluorouracil in DNA. Biochemistry 50 (5):618-27
  53. Labianca R, Marsoni S, Pancera G, Torri V, Zaniboni A (GIVIO,Italy), Erlichman C, Pater J, Shepherd L, Zee B (NCIC-CTG, Canada), Seitz J F, Milan C, Pignon J P (FFCD, France).(Hrsg.) 1995. Efficacy of adjuvant fluorouracil and folinic acid in Kolon cancer. International Multicentre Pooled Analysis of Kolon Cancer Trials (IMPACT) investigators. Lancet 345 (8955):939-44 Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24 (33):5313-27
  54. Pox CP, Altenhofen L, Brenner H, Theilmeier A, Stillfried D von, Schmiegel W. 2012. Efficacy of a nationwide screening Kolonoscopy program for colorectal cancer. Gastroenterology 142 (7):1460-7.e2
  55. Noor F, Kinscherf R, Bonaterra GA, Walczak S, Wölfl S, Metzler-Nolte N. 2009. Enhanced cellular uptake and cytotoxicity studies of organometallic bioconjugates of the NLS peptide in Hep G2 cells. Chembiochem : a European journal of chemical biology 10 (3):493-502
  56. Park J, Collins JM, Gazdar AF, Allegra CJ, Steinberg SM, Greene RF, Kramer BS. 1988. Enhancement of fluorinated Pyrimidine-Induced Cytotoxicity by Leucovorin in Human Colorectal Carcinoma Cell Lines. JNCI Journal of the National Cancer Institute 80 (19):1560-64
  57. Rosemeyer H, Malecki E, Werz E, Korneev S, Gall K. Eur. Pat. Appl. EP 12 186 576.0, 2012
  58. Kish JA, Wolf M, Crawford ED, Leimert JT, Bueschen A, Neefe JR, Flanigan RC. 1994. Evaluation of low dose continuous infusion 5-fluorouracil in patients with advanced and recurrent renal cell carcinoma. A Southwest Oncology Group Study. Cancer 74 (3):916-19
  59. Da Violante G, Zerrouk N, Richard I, Provot G, Chaumeil JC, Arnaud P. 2002. Evaluation of the cytotoxicity effect of dimethyl sulfoxide (DMSO) on Caco2/TC7 colon tumor cell cultures. Biological & pharmaceutical bulletin 25 (12):1600-03
  60. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, et al. 2014. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 25 (7):1346-55
  61. Heidelberger C, Chaudhuri NK, Dannbeg P, Mooren D, Griesbach L, et al. 1957. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179 (4561):663-66
  62. Heidelberger C, Griesbach L, Cruz O, Schnitzer RJ, Grunberg E. 1958. Fluorinated pyrimidines. VI. Effects of 5-fluorouridine and 5-fluoro-2'-deoxyuridine on transplanted tumors. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 97 (2):470-75
  63. Swain SM, Lippman ME, Egan EF, Drake JC, Steinberg SM, Allegra CJ. 1989. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 7 (7):890-99
  64. Falcone A, Cremolini C, Masi G, Lonardi S, Zagonel V, et al. FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group [Abstract]. In ASCO Annual Meeting; 31 May-4 June 2013; Chicago, IL
  65. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, et al. 2014. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. European journal of cancer (Oxford, England : 1990) 50 (1):57-63
  66. Jemal A, Bray F, Center mm, Ferlay J, Ward E, Forman D. 2011. Global cancer statistics. CA: a cancer journal for clinicians 61 (2):69-90
  67. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. 2010. Hereditary and familial Kolon cancer. Gastroenterology 138 (6):2044-58
  68. Spring KJ, Zhao ZZ, Karamatic R, Walsh MD, Whitehall VL, et al. 2006. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing Kolonoscopy. Gastroenterology 131 (5):1400-07
  69. Chipuk JE, Green DR. 2008. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends in cell biology 18 (4):157-64
  70. Majumdar SR, Fletcher RH, Evans AT. 1999. How does colorectal cancer present? Symptoms, duration, and clues to location. The American journal of gastroenterology 94 (10):3039-45
  71. Chu E, Voeller DM, Jones KL, Takechi T, Maley GF, et al. 1994. Identification of a thymidylate synthase ribonucleoprotein complex in human Kolon cancer cells. Molecular and cellular biology 14 (1):207-13
  72. Stern-Straeter J, Bonaterra GA, Hörmann K, Kinscherf R, Goessler UR. 2009. Identification of valid reference genes during the differentiation of human myoblasts. BMC molecular biology 10:66
  73. Malecki E, Viere R, Rosemeyer H. 2013b. Immobilization of 5-fluorouridine on chitosan. Chemistry & biodiversity 10 (10):1828-41
  74. Johnston PG, Drake JC, Trepel J, Allegra CJ. 1992. Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracilsensitive and -resistant human cancer cell lines. Cancer research 52 (16):4306-12
  75. Aherne GW, Hardcastle A, Raynaud F, Jackman AL. 1996. Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD1694) and a nonpolyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells. Biochemical pharmacology 51 (10):1293-301
  76. Herold G. 2015. Innere Medizin. Eine vorlesungsorientierte Darstellung : unter Berücksichtigung des Gegenstandskataloges für die Ärztliche Prüfung : mit ICD 10- Schlüssel im Text und Stichwortverzeichnis. S. 488-496. Köln: Herold. 2015th ed.
  77. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, et al. 2000. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355 (9209):1041-47
  78. Higuchi R, Fockler C, Dollinger G, Watson R. 1993. Kinetic PCR analysis: real-time monitoring of DNA amplification reactions. Bio/technology (Nature Publishing Company) 11 (9):1026-30
  79. Ahnen DJ, Feigl P, Quan G, Fenoglio-Preiser C, Lovato LC, et al. 1998. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer research 58 (6):1149-58
  80. O'Connell JB, Maggard MA, Ko CY. 2004. Kolon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. Journal of the National Cancer Institute 96 (19):1420-25
  81. Becker N, Wahrendorf J. Krebsatlas der Bundesrepublik Deutschland 1981-1990, Springer, Berlin Heidelberg New York 1998, : Fortschreibung im Internet: www.krebsatlas.de. www.krebsatlas.de
  82. Sengupta S, Tjandra JJ. 2001. Local excision of rectal cancer: what is the evidence? Diseases of the Kolon and rectum 44 (9):1345-61
  83. Nagtegaal ID, van de Velde, Cornelius J H, Marijnen, Corrie A M, van Krieken, Jan H J M, Quirke P. 2005. Low rectal cancer: a call for a change of approach in abdominoperineal resection. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23 (36):9257-64
  84. Stintzing S. 2014. Management of colorectal cancer. F1000prime reports 6:108
  85. Khosravi Shahi P, Díaz Muñoz de la Espada, V M, García Alfonso P, Encina García S, Izarzugaza Perón Y, et al. 2007. Management of gastric adenocarcinoma. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 9 (7):438-42
  86. Santi DV, McHenry CS, Sommer H. 1974. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13 (3):471-81
  87. Bonaterra GA, Kelber O, Weiser D, Kinscherf R. 2013. Mechanisms of the antiproliferative and anti-inflammatory effects of the herbal fixed combination STW 5 (Iberogast®) on Kolon adenocarcinoma (HT29) cells in vitro. Phytomedicine : international journal of phytotherapy and phytopharmacology 20 (8-9):691-98
  88. Giovannucci E. 2002. Modifiable risk factors for Kolon cancer. Gastroenterology clinics of North America 31 (4):925-43
  89. West NP, Anderin C, Smith, K J E, Holm T, Quirke P. 2010. Multicentre experience with extralevator abdominoperineal excision for low rectal cancer. The British journal of surgery 97 (4):588-99
  90. Andersen CL, Jensen JL, Ørntoft TF. 2004. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and Kolon cancer data sets. Cancer research 64 (15):5245-50
  91. Malecki E. 2013. Nucleolipids and Lipo-Oligonucleotides of 5-Fluorouridine: Synthesis, Biological Applications and Immobilization. Osnabrück
  92. Malecki E, Ottenhaus V, Werz E, Knies C, Montilla Martinez M, Rosemeyer H. 2014. Nucleolipids of the cancerostatic 5-fluorouridine: synthesis, adherence to oligonucleotides, and incorporation in artificial lipid bilayers. Chemistry & biodiversity 11 (2):217-32
  93. Köstler K, Werz E, Malecki E, Montilla-Martinez M, Rosemeyer H. 2013. Nucleoterpenes of thymidine and 2'-deoxyinosine: synthons for a biomimetic lipophilization of oligonucleotides. Chemistry & biodiversity 10 (1):39-61
  94. Malecki E, Rosemeyer H. 2010. O-2', 3'-Ketal-Nucleolipids of the Cytostatic 5- Fluorouridine: Synthesis, Lipophilicity, and Acidic Stability. Helvetica Chimica Acta (93 (8)):1500-12
  95. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, et al. 2004. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for Kolon cancer. The New England journal of medicine 350 (23):2343-51
  96. Peters GJ, ed. 1995. Oxford Textbook of Oncology, Antimetabolites. pp. 524-552. Oxford
  97. Lowe SW, Ruley HE, Jacks T, Housman DE. 1993. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74 (6):957-67
  98. Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P, Green DR. 2000. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. The Journal of biological chemistry 275 (10):7337-42
  99. Wolff S, Erster S, Palacios G, Moll UM. 2008. p53's mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity. Cell research 18 (7):733-44
  100. Weeks JC, Catalano PJ, Cronin A, Finkelman MD, Mack JW, Keating NL, Schrag D. 2012. Patients' expectations about effects of chemotherapy for advanced cancer. The New England journal of medicine 367 (17):1616-25
  101. Busca A, Saxena M, Iqbal S, Angel J, Kumar A. 2014. PI3K/Akt regulates survival during differentiation of human macrophages by maintaining NF-κB-dependent expression of antiapoptotic Bcl-xL. Journal of leukocyte biology 96 (6):1011-22
  102. Palmqvist R, Engarås B, Lindmark G, Hallmans G, Tavelin B, et al. 2003. Prediagnostic levels of carcinoembryonic antigen and CA 242 in colorectal cancer: a matched case-control study. Diseases of the Kolon and rectum 46 (11):1538-44
  103. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. 2004. Preoperative versus postoperative chemoradiotherapy for rectal cancer. The New England journal of medicine 351 (17):1731-40
  104. Kyle SM, Isbister WH, Yeong ML. 1991. Presentation, duration of symptoms and staging of colorectal carcinoma. The Australian and New Zealand journal of surgery 61 (2):137-40
  105. Wettergren Y, Carlsson G, Odin E, Gustavsson B. 2012. Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5-fluorouracil-based chemotherapy. Cancer 118 (11):2935-43
  106. Willett CG, Badizadegan K, Ancukiewicz M, Shellito PC. 1999. Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Diseases of the Kolon and rectum 42 (2):167-73
  107. Kwok SP, Lau WY, Leung KL, Liew CT, Li AK. 1996. Prospective analysis of the distal margin of clearance in anterior resection for rectal carcinoma. The British journal of surgery 83 (7):969-72
  108. Sommer H, Santi DV. 1974. Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5-fluoro-2'- deoxyuridylate and methylenetetrahydrofolate. Biochemical and biophysical research communications 57 (3):689-95
  109. Scheithauer W, Rosen H, Kornek GV, Sebesta C, Depisch D. 1993. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ (Clinical research ed.) 306 (6880):752-55
  110. Houghton JA, Tillman DM, Harwood FG. 1995. Ratio of 2'-deoxyadenosine-5'- triphosphate/thymidine-5'-triphosphate influences the commitment of human Kolon carcinoma cells to thymineless death. Clinical cancer research : an official journal of the American Association for Cancer Research 1 (7):723-30
  111. Wang W, Yang Y, Zhao Y, Zhang T, Liao Q, Shu H. 2014. Recent studies of 5- fluorouracil resistance in pancreatic cancer. World journal of gastroenterology : WJG 20 (42):15682-90
  112. Kirke R, Rajesh A, Verma R, Bankart, Michael J G. 2007. Rectal cancer: incidence of pulmonary metastases on thoracic CT and correlation with T staging. Journal of computer assisted tomography 31 (4):569-71
  113. Macrae FA, St John, D J. 1982. Relationship between patterns of bleeding and Hemoccult sensitivity in patients with colorectal cancers or adenomas. Gastroenterology 82 (5 Pt 1):891-98
  114. Patton JR. 1993. Ribonucleoprotein particle assembly and modification of U2 small nuclear RNA containing 5-fluorouridine. Biochemistry 32 (34):8939-44
  115. Salup RR, Herberman RB, Wiltrout RH. 1985. Role of natural killer activity in development of spontaneous metastases in murine renal cancer. The Journal of urology 134 (6):1236-41
  116. Redman CM, Avellino G, Yu S. 1983. Secretion of proalbumin by canavanine-treated Hep-G2 cells. The Journal of biological chemistry 258 (6):3446-52
  117. Albert A, ed. 1985. Selected Toxicity. pp. 60, 125-126. London, New York: Champman and Hall
  118. Noffsinger AE. 2009. Serrated polyps and colorectal cancer: new pathway to malignancy. Annual review of pathology 4:343-64
  119. Horton KM, Abrams RA, Fishman EK. 2000. Spiral CT of Kolon cancer: imaging features and role in management. Radiographics : a review publication of the Radiological Society of North America, Inc 20 (2):419-30
  120. Collins PD, Mpofu C, Watson AJ, Rhodes JM. 2006. Strategies for detecting Kolon cancer and/or dysplasia in patients with inflammatory bowel disease. The Cochrane database of systematic reviews (2):CD000279
  121. Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D. 1990. Structural and functional analysis of the human thymidylate synthase gene. The Journal of biological chemistry 265 (33):20277-84
  122. Rutman RJ, Cantarow A, Paschkis KE. 1954. Studies in 2-acetylaminofluorene carcinogenesis. III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma. Cancer research 14 (2):119-23
  123. Chaudhuri NK, Montag BJ, Heidelberger C. 1958. Studies on fluorinated pyrimidines. III. The metabolism of 5-fluorouracil-2-C14 and 5-fluoroorotic-2-C14 acid in vivo. Cancer research 18 (3):318-28
  124. Dannberg PB, Montag BJ, Heidelberger C. 1958. Studies on fluorinated pyrimidines. IV. Effects on nucleic acid metabolism in vivo. Cancer research 18 (3):329-34
  125. Bosch L, Harbers E, Heidelberger C. 1958. Studies on fluorinated pyrimidines. V. Effects on nucleic acid metabolism in vitro. Cancer research 18 (3):335-43
  126. Mader RM, Kalipciyan M, Ohana P, Hochberg A, Steger GG. 2011. Suicide activation in a 5-fluorouracil resistant Kolon cancer model in vitro. International journal of clinical pharmacology and therapeutics 49 (1):69-70
  127. Chen HS, Sheen-Chen SM. 2000. Synchronous and "early" metachronous colorectal adenocarcinoma: analysis of prognosis and current trends. Diseases of the Kolon and rectum 43 (8):1093-99
  128. Duchinsky R, Pleven E, Heidelberger C. Synthesis of 5-fluoropyrimidines. Journal of the American Chemical Society 1957 (79):4559-60
  129. Malecki E, Farhat A, Bonaterra GA, Röthlein D, Wolf M, et al. 2013a. Synthesis of 5- fluorouridine nucleolipid derivatives and their cytostatic/cytotoxic activities on human HT-29 Kolon carcinoma cells. Chemistry & biodiversity 10 (12):2235-46
  130. Werz E, Viere R, Gassmann G, Korneev S, Malecki E, Rosemeyer H. 2013. Synthesis of Thymidine, Uridine, and 5-Methyluridine Nucleolipids: Tools for a Tuned Lipophilization of Oligonucleotides. HCA 96 (5):872-88
  131. Wolpin BM, Mayer RJ. 2008. Systemic treatment of colorectal cancer. Gastroenterology 134 (5):1296-310
  132. Jackson, R. C. & Grindley, G. B., ed. 1984. The Biochemical Basis for Methotrxate Cytotoxicity. 289-315. New York: Academic
  133. Marin-Vicente C, Lyutvinskiy Y, Romans Fuertes P, Zubarev RA, Visa N. 2013. The effects of 5-fluorouracil on the proteome of Kolon cancer cells. Journal of proteome research 12 (4):1969-79
  134. Naguib A, Gay L J, Arends M J, Mitrou P N. 2012. The Molecular Genetic Events in Coorectal Cancer and Diet: INTECH Open Access Publisher
  135. Nussbaum N, Altomare I. 2015. The neoadjuvant treatment of rectal cancer: a review. Current oncology reports 17 (3):434
  136. Schroeder A, Mueller O, Stocker S, Salowsky R, Leiber M, et al. 2006. The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC molecular biology 7:3
  137. Brat DJ, Bellail AC, Van Meir, Erwin G. 2005. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncology 7 (2):122-33
  138. Amaral JD, Xavier JM, Steer CJ, Rodrigues CM. 2010. The role of p53 in apoptosis. Discovery medicine 9 (45):145-52
  139. Longley DB, Boyer J, Allen WL, Latif T, Ferguson PR, et al. 2002. The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates. Cancer research 62 (9):2644-49
  140. Al-Nasiry S, Geusens N, Hanssens M, Luyten C, Pijnenborg R. 2007. The use of Alamar Blue assay for quantitative analysis of viability, migration and invasion of choriocarcinoma cells. Human reproduction (Oxford, England) 22 (5):1304-09
  141. Copur S, Aiba K, Drake JC, Allegra CJ, Chu E. 1995. Thymidylate synthase gene amplification in human Kolon cancer cell lines resistant to 5-fluorouracil. Biochemical pharmacology 49 (10):1419-26
  142. Sobin LH, Gospodarowicz MK, Wittekind C. 2009. TNM classification of malignant tumours. Chichester, West Sussex, UK, Hoboken, NJ: Wiley-Blackwell. 7th ed
  143. Miyashita T, Reed JC. 1995. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80 (2):293-99
  144. Pettersen HS, Visnes T, Vågbø CB, Svaasand EK, Doseth B, et al. 2011. UNG-initiated base excision repair is the major repair route for 5-fluorouracil in DNA, but 5- fluorouracil cytotoxicity depends mainly on RNA incorporation. Nucleic acids research 39 (19):8430-44
  145. Alberts SR. 2012. Update on the optimal management of patients with colorectal liver metastases. Critical reviews in oncology/hematology 84 (1):59-70
  146. Idziorek T, Estaquier J, Bels F de, Ameisen JC. 1995. YOPRO-1 permits cytofluorometric analysis of programmed cell death (apoptosis) without interfering with cell viability. Journal of immunological methods 185 (2):249-58


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