14 research outputs found

    The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro

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    The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro. Abou El Hassan MA, Verheul HM, Jorna AS, Schalkwijk C, van Bezu J, van der Vijgh WJ, Bast A. Department of Medical Oncology, Free University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. [email protected] Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 micro M monoHER. Resting (confluent) HUVECs were incubated with (0.5-25 micro M) doxorubicin with(out) monoHER (0.2-1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC(50)=60.0+/-20.8 nM) than resting cells (LC(50)=4.0+/-0.3 micro M). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of > or =0.4 micro M (P=0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (< or =25 micro M, P<0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in viv

    Prospects for bioreductive drug development

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    Bioreductive drugs are inactive prodrugs that are converted into potent cytotoxins under conditions of either low oxygen tension or in the presence of high levels of specific reductases. The biochemical basis for selectivity relies on the ability of oxygen to reverse the activation process and the presence of elevated reductase levels in some tumour types. Key criteria for an ideal bioreductive drug should include poor activity against aerobic cells, activation over a broad range of oxygen tensions and, penetration through the aerobic fraction of cells. In addition, the active drug should be capable of killing non-proliferating cells. Numerous compounds are currently at various stages of drug development but Mitomycin C, which is generally considered to be the prototype bioreductive drug, is the only one in clinical use today. Of the drugs currently being evaluated clinically, tirapazamine has definite clinical activity against a variety of solid tumours when used in combination with cisplatin. Other drugs, such as EO9 and various nitroimidazoles, have not been impressive in the clinic and further development is required to improve properties such as drug delivery in the case of indoloquinones. A novel approach to exploiting tumour hypoxia is the development of a gene-directed enzyme prodrug therapy (GDEPT) strategy, where a gene encoding for a prodrug activating enzyme has been placed under the control of a hypoxia responsive promoter sequence. It is generally recognised that bioreductive drugs must be directed towards patients whose tumours have hypoxic regions or have appropriate enzymological characteristics. In terms of identifying tumour hypoxia, there has been considerable progress in the development of nitroimidazole based hypoxia markers that can be detected either via non-invasive or invasive procedures. Another strategy currently undergoing preclinical evaluation is the use of agents that modulate tumour blood flow and synergistic effects have been reported between bioreductive drugs and photodynamic therapy or inhibitors of nitric oxide synthase for example. The development of clinically useful bioreductive drugs depends therefore on the expertise of scientists and clinicians with varying backgrounds. The purpose of this review is to describe and critically assess recent developments in this field, with particular emphasis being placed on drug development and strategies aimed at optimising bioreductive drug activity
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