Estudio de la actividad citotóxica e inmunomodulatoria del compuesto PM01183 (Lurbinectedin) sobre células luecocitarias normales y malignas
Lurbinectedin (Lur) is a synthetic alkaloid that induces DNA damage on both, quiescent and proliferative cells and is currently in phase II/III clinical trials for solid tumors. The main goals of this thesis were to evaluate the cytotoxic capacity of Lur on circulating mononuclear cells from CLL pat...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2769 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2769.dir/2769.PDF |
| Aporte de: |
| Sumario: | Lurbinectedin (Lur) is a synthetic alkaloid that induces DNA damage on both, quiescent and proliferative cells and is currently in phase II/III clinical trials for solid tumors. The main goals of this thesis were to evaluate the cytotoxic capacity of Lur on circulating mononuclear cells from CLL patients and healthy donors, and to determine whether it could alter the cross-talk of CLL cells with the tumor microenvironment. We found that Lur induced a dose- and time-dependent death of all cell types evaluated, being B cells, monocytes and monocytic myeloid derived suppressor cells the most susceptible populations. Interestingly, nurse like cells differentiated in vitro from monocytes were comparably resistant to Lur. Moreover, at sub-apoptotic doses, Lur decreased the expression of CCR7 on CLL cells and impaired their migration towards CCL19 or CCL21. Remarkably, low concentrations of Lur stimulated the synthesis of pro-IL1? in monocytes and macrophages. Altogether, these results indicate that Lur might have antitumor activity in CLL due to its direct action on the leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lur as a potential therapy for CLL. |
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