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3 Acta Biochimica Polonica

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Salmonella and cancer: from pathogens to therapeutics

100%

Chorobik P. , Czaplicki D. , Ossysek K. , Bereta J.

nr 3

285-297

Bacterial cancer therapy is a concept more than 100 years old - yet, all things considered, it is still in early development. While the use of many passive therapeutics is hindered by the complexity of tumor biology, bacteria offer unique features that can overcome these limitations. Microbial metabolism, motility and sensitivity can lead to site-specific treatment, highly focused on the tumor and safe to other tissues. Activation of tumor-specific immunity is another important mechanism of such therapies. Several bacterial strains have been evaluated as cancer therapeutics so far, Salmonella Typhimurium being one of the most promising. S. Typhimurium and its derivatives have been used both as direct tumoricidal agents and as cancer vaccine vectors. VNP20009, an attenuated mutant of S. Typhimurium, shows significant native toxicity against murine tumors and was studied in a first-in-man phase I clinical trial for toxicity and anticancer activity. While proved to be safe in cancer patients, insufficient tumor colonization of VNP20009 was identified as a major limitation for further clinical development. Antibody-fragment-based targeting of cancer cells is one of the few approaches proposed to overcome this drawback.

Antibody-based antiangiogenic and antilymphangiogenic therapies to prevent tumor growth and progression

75%

Bzowska M. , Mężyk-Kopeć R. , Próchnicki T. , Kulesza M. , Klaus T. , Bereta J.

nr 3

263-275

Blood and lymphatic vessel formation is an indispensable factor for cancer progression and metastasis. Therefore, various strategies designed to block angiogenesis and lymphangiogenesis are being investigated in the hope to arrest and reverse tumor development. Monoclonal antibodies, owing to their unequalled diversity and specificity, might be applied to selectively inhibit the pathways that cancer cells utilize to build up a network of blood vessels and lymphatics. Among the possible targets of antibody-based therapies are proangiogenic and prolymphangiogenic growth factors from the VEGF family and the receptors to which they bind (VEGFRs). Here, we present molecular mechanisms of angiogenesis and lymphangiogenesis exploited by tumors to progress and metastasise, with examples of antibody-based therapeutic agents directed at interfering with these processes. The expanding knowledge of vascular biology helps to explain some of the problems encountered in such therapies, that arise due to the redundancy in signaling networks controlling the formation of blood and lymphatic vessels, and lead to tumor drug resistance. Nonetheless, combined treatments and treatments focused on newly discovered proangiogenic and prolymphangiogenic factors give hope that more prominent therapeutic effects might be achieved in the future.

Exogenous nitric oxide inhibits shedding of ADAM17 substrates

75%

Bzowska M. , Stalińska K. , Mężyk-Kopeć R. , Wawro K. , Duda K. , Das S. , Bereta J.

nr 2

325-335

Both ADAM17, the secretase responsible for the shedding of ectodomains of numerous membrane proteins including TNF and its receptors, as well as nitric oxide synthesized by inducible nitric oxide synthase play regulatory roles in inflammation and tumor progression. We analyzed the effect of endogenous and exogenous nitric oxide on the expression and activity of ADAM17 in murine endothelial cells and a monocyte/macrophage cell line. We found that endogenous nitric oxide influenced neither ADAM17 mRNA level nor the shedding of two ADAM17 substrates, TNF and TNFR1. Exogenous NO significantly diminished the release of TNF and TNFR1 without affecting the ADAM17 transcript level. Our data seem contrary to a previous report that showed the activation of ADAM17 by nitric oxide (Zhang et al., 2000, J Biol Chem 275: 15839-15844). We discuss potential mechanisms of NO-mediated inhibition of ectodomain shedding and possible reasons of discrepancy between our results and the previous report.