Monika Jagiello

Polish Academy of Sciences, Warsaw, Masovian Voivodeship, Poland

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Publications (5)7.96 Total impact

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    ABSTRACT: Drugs used in chemotherapy give undesirable side effects, e.g., cardiotoxicity, leucopenia, hair loss and others. Covalent binding of a drug with a carrier may change its biodistribution, elimination and/or rate of transformation in the organism. The aim of this work was to synthesize conjugates of anticancer drug - raltitrexed (RTX) with lysozyme, bovine serum albumin (BSA), and dextran T40 and to investigate their cytotoxicity and influence on the cell cycle in comparison with the free drug. Before conjugation RTX was transformed into anhydride by treatment with dicyclohexylcarbodiimide in dimethylformamide. Activated RTX was added into aqueous solution of carriers at different pH (from 8.5 to 10.5) for 3 to 15 min. The reaction was stopped by reducing the pH to 7.0. Maximum yield of the reaction was obtained at pH 10 for BSA as well as for dextran. The highest level of substitution was obtained after 5 min of the reaction. In in vitro experiments on three cell lines: SW707, LoVo and A549, all conjugates tested had up to a few hundred times higher IC(50) than the free drug. Interestingly, it was noticed that the conjugates based on dextran and albumin were more cytotoxic than the free drug in the highest concentrations tested (1000 and 10000 ng/ml). The influence of RTX and the conjugates on SW707 cell cycle was studied. RTX blocked the cell cycle mostly in the G(0)-G(1) and S phase and increased the percentage of apoptotic cells. Cells in the G(2)-M phase were not observed. The conjugates blocked the cell cycle in the S phase and decreased the percentage of cells in the G(0)-G(1) phase.
    Acta biochimica Polonica 01/2010; 57(1):83-7. · 1.19 Impact Factor
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    ABSTRACT: Conjugation of anticancer drugs with different carriers has been extensively studied recently as a potential method of obtaining improved drug forms. The conjugation often results in the increase of the therapeutic effect, alteration of a toxicity profile, and/or selective targeting of therapeutic agent to the tissue of interest. We have synthesized mannan-methotrexate conjugate by means of methotrexate anhydride and studied its antitumor properties both in vitro and in vivo in comparison with free methotrexate. Mannan-methotrexate conjugate showed significantly improved antitumor activity compared to free methotrexate in the model of P388 mouse leukemia disseminated in the peritoneal cavity treated with intraperitoneally injected chemotherapy. Conversely, the antitumor effects of free methotrexate and mannan-methotrexate conjugate were comparable when leukemia was implanted subcutaneously and chemotherapy agents were administered intravenously. These results suggest that mannan-methotrexate conjugate should be further investigated as a potential therapeutic agent for intraperitoneally disseminated tumors.
    Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 02/2007; 16(9):415-21. · 1.63 Impact Factor
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    ABSTRACT: Methotrexate (MTX) is widely used in the treatment of a number of oncological and hematological diseases. Due to its known limitations, MTX is often conjugated with different carriers to obtain amended forms of the drug. In this study, the potential influence of the substitution level (loading ratio) of the dextran T10- and T40-based MTX conjugates (D-MTX) on their properties were investigated in vitro and in vivo. The clear dependence of the in vitro antiproliferative effect on the substitution level was established only in the case of the dextran T10-based preparations (T10-MTX conjugates). Conjugates with the higher substitution level had the lower antiproliferative effect. For the dextran T40-based (T40-MTX conjugates) set no similar relationship was observed in the tested range of substitution levels, nor was any dependence observed between the biological properties of the D-MTX preparations in vivo and their substitution levels. However, the difference between the two conjugates was well pronounced in a multiple-dose schedule, when the advantage of T40-MTX over T10-MTX was cumulative during the prolonged course of administration.
    Anticancer research 01/2006; 26(3A):2179-86. · 1.71 Impact Factor
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    ABSTRACT: Methotrexate (MTX) is widely utilized in the clinical treatment of many forms of cancer. However, the drug has a short plasma half-life and causes toxic effects on normal proliferating cells. Conjugation with carriers is a possible way to alter these disadvantageous pharmacokinetics. Our aim was to synthesize dextran-MTX (D-MTX) conjugates, using carriers with molecular weights (Mw) ranging from 10 kDa to 500 kDa. Their in vitro and in vivo properties were compared with free MTX. The in vitro studies revealed that D-MTX conjugates had 4- to 10-fold lower antiproliferative effects against neoplastic cell lines compared to free MTX. There was a negative relationship between the Mw of the carrier and the antiproliferative effect of the respective conjugate. The data obtained in a mouse leukemia P388 in vivo model suggested that a lower in vitro antiproliferative effect of the conjugates does not result in diminished antileukemic activity in vivo. The toxicity of the conjugates was greater in comparison with the parent drug and tended to rise with increasing Mw. However, no superiority over free MTX in terms of an antileukemic effect was demonstrated. In particular, the D-MTX conjugate based on the dextran with Mw 10 kDa showed a comparable antileukemic effect with an even lower toxicity than that of free MTX. The data suggest that at least the toxicity of conjugates is dependent on the Mw of the carrier. This fact should be taken into account when designing new anticancer polymer-drug compounds.
    Anticancer research 01/2006; 26(2A):1135-43. · 1.71 Impact Factor
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    ABSTRACT: The aim of the study was to compare the antileukemic activity of methotrexate (MTX) conjugates with native and glycated fibrinogen. We expected that conjugates based on glycated fibrinogen would reveal higher antileukemic activity because of decreased plasmin digestibility and a higher retention rate of glycated fibrinogen in the body. Fibrinogen was glycated using a high-temperature procedure at 65-85 degrees C. Glycated fibrinogens were examined with respect to their ability to clot and susceptibility to plasmin digestion. Native fibrinogen (F) and fibrinogens glycated at 65 and 73 degrees C (F65 and F73) were conjugated with MTX and tested in mice bearing P388 leukemia, at a dose of 40 mg of MTX per kg of body weight. Glycated fibrinogens retained their ability to clot. Compared to native fibrinogen, they were more resistant to digestion by plasmin. All tested conjugates revealed higher antitumor activity than the free drug. Increases in average lifespan over the control group were 34% for free MTX, 137% for F-MTX, 151% for F65-MTX and 91% for F73-MTX. The differences between the antitumor activities of all conjugates were not statistically significant. It seems necessary to compare the antitumor activities of MTX conjugates based on native and glycated fibrinogen in different tumor models, to demonstrate the expected differences.
    Anticancer research 01/2005; 25(3B):2229-34. · 1.71 Impact Factor

Publication Stats

22 Citations
7.96 Total Impact Points

Institutions

  • 2005–2010
    • Polish Academy of Sciences
      • • Ludwik Hirszfeld Institute of Immunology and Experimental Therapy
      • • Laboratory of Biomedical Optics
      • • Zakład Farmakologii Doświadczalnej
      Warsaw, Masovian Voivodeship, Poland