In this study, we evaluated the activity of two novel pyrazolopyrimidine derivs. (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concns. of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 μM Si 34 detd. a decrease of cell counts by ∼25% and ∼75% compared with those of control cells resp. Similar findings were obsd. using Si 35. Treatment with both Si 34 and Si 35 at 10 μM increased cell mortality also (∼29% and ∼18% resp.). At these concns., a decrease in cyclin D1 levels was obsd. To improve the biopharmaceutical properties, a liposome formulation was prepd. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 μM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were assocd. with weak apoptotic death. Inhibition of epidermal growth factor-stimulated src and ERK phosphorylation, as well as redn. of migration properties of ARO cells was also obsd. Moreover, the growth of tumor xenografts induced in severe combined immunodeficiency (SCID) mice was inhibited by i.v. administration of 25-50 mg/kg of the drug liposomal formulation. In conclusion, the liposomal prepn. of this novel pyrazolopyrimidine deriv. appears to be a promising tool for the treatment of anaplastic thyroid cancer.
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