RESUMEN
Integrins are associated with tumour cell survival and progression, and their expression has been shown to be increased in tumours. Thus, four novel conjugates of the tripeptide integrin ligand Arg-Gly-Asp (RGD) and the cytotoxic agent paclitaxel (cRGD-PTX) were prepared to investigate the potential of the multivalent presentation of the RGD moiety in improving the antitumor efficacy of PTX by tumour targeting. PTX was conjugated to two or four integrin recognizing ligands. The influence of multivalent presentation on in vitro αvß3-receptor affinity was confirmed. For all the conjugates compared to the previously synthesized monovalent counterparts, an enhancement of the binding strength was observed; this behaviour was more pronounced when considering the tetravalent presented RGD-conjugate. Cell growth inhibition assays on a panel of human tumour cell lines showed remarkable cytotoxic activity for all conjugates with IC50 values in a nanomolar range. Among the four conjugates, the bivalent derivative 3b was selected for in vivo studies in an ovarian carcinoma cell model xenografted in immunodeficient mice. A marked antitumor activity was observed, similar to that of PTX, but with a much more favourable toxicity profile. Overall, the novel cRGD-PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted anti-tumour therapy.
Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Paclitaxel/síntesis química , Paclitaxel/farmacología , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Multimerización de Proteína , Animales , Antineoplásicos/farmacología , Biotinilación , Línea Celular Tumoral , Femenino , Humanos , Integrina alfaVbeta3/metabolismo , Ratones Desnudos , Péptidos Cíclicos/química , Vitronectina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Applications of laser therapy in biostimulation and healing injured tissues are widely described in medical literature. The present study focuses on the effects of laser irradiation on the growth rate and differentiation of human osteoblast-like cells seeded on titanium or zirconia surfaces. Cells were laser irradiated with low therapeutical doses at different intervals and the effects of irradiation were evaluated at each time-point. After 3 hours lasered cells showed an enhanced mitogen activity compared to non-lasered control cells and a higher alkaline phosphatase activity, marker of bone formation. At the same time, the mRNA of RUNX2 and OSTERIX, two genes involved in osteoblast differentiation, showed a clear decrease in lasered cells. This reached the lowest value 6 to 12 hours after irradiation, after which the transcripts started to increase, indicating that the laser treatment did promote the osteogenic potential of growth-induced cells. These results indicate that Low Level Laser Treatment (LLLT) stimulates osteogenic cell proliferation.
Asunto(s)
Terapia por Luz de Baja Intensidad , Osteoblastos/efectos de la radiación , Osteogénesis/efectos de la radiación , Adulto , Matriz Ósea/efectos de la radiación , Proliferación Celular/efectos de la radiación , Respiración de la Célula/efectos de la radiación , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Humanos , Persona de Mediana Edad , Factor de Transcripción Sp7 , Factores de Transcripción/genéticaRESUMEN
El objetivo de este trabajo fue estudiar los efectos de la administración de clorato de níquel en el epitelio de revestimiento y hueso palatino de fetos de ratas. Fue administrada una inyección intraperitoneal de clorato de níquel (30mg/kg de peso corporal) en el 10º día de preñez. Las ratas fueron sacrigicadas en el 20º día y, los fetos fueron inmersos en solución fijadora. Las cabezas de los fetos control y tratados fueron incluidas, cortadas y coloradas para la aplicación de los análisis morfométricos y estereológicos. Se utilizó el test no paramétrico de Mann-Whitney. Los resultados mostraron alteración en el epitelio de revestimiento de los palatos duro y blando y disminución en la densidad de trabéculas óseas. Estos resultados sugieren aspectos de inmaturidad en el feto tratado (AU)
