Browsing by Author "Markovic, I.D. (7004033826)"

Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance. © E.S.I.F.T. srl.

Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance. © E.S.I.F.T. srl.

The aim of this study was to investigate the transport of tiazofurin (2-β-D-ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) using brain vascular perfusion and capillary depletion method in the guinea pig. Values for volume of distribution of [3H] tiazofurin in brain increased slowly and almost linearly in time, from 1% of its plasma concentration at 1 min to 5% after 15 min of perfusion. Unidirectional transport constant K(in) was 2.61 ± 0.21 x 10-3 ml/min/g. According to these results, it is evident that tiazofurin slowly penetrates the BBB. Addition of unlabeled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labeled tiazofurin (K(in) = 0.77 ± 0.1 x 10-3 ml/min/g). Therefore, penetration of tiazofurin from blood into brain seems to be a saturable process. Presence of potential inhibitors of tiazofurin blood-to-brain transport (adenosine and dipyridamole) did not cause complete inhibition of tiazofurin brain uptake. Thus, it could be assumed that transport of tiazofurin from blood into brain is only partially mediated by the nucleosides transport system. The results obtained using capillary depletion method show that tiazofurin that passes across the BBB is accumulated mostly in the brain tissue and not in brain capillaries endothelial cells.

The aim of this study was to investigate the transport of tiazofurin (2-β-D-ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) using brain vascular perfusion and capillary depletion method in the guinea pig. Values for volume of distribution of [3H] tiazofurin in brain increased slowly and almost linearly in time, from 1% of its plasma concentration at 1 min to 5% after 15 min of perfusion. Unidirectional transport constant K(in) was 2.61 ± 0.21 x 10-3 ml/min/g. According to these results, it is evident that tiazofurin slowly penetrates the BBB. Addition of unlabeled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labeled tiazofurin (K(in) = 0.77 ± 0.1 x 10-3 ml/min/g). Therefore, penetration of tiazofurin from blood into brain seems to be a saturable process. Presence of potential inhibitors of tiazofurin blood-to-brain transport (adenosine and dipyridamole) did not cause complete inhibition of tiazofurin brain uptake. Thus, it could be assumed that transport of tiazofurin from blood into brain is only partially mediated by the nucleosides transport system. The results obtained using capillary depletion method show that tiazofurin that passes across the BBB is accumulated mostly in the brain tissue and not in brain capillaries endothelial cells.

Tiazofurin (TZF- beta-D-ribofuranosyl thiazole-4-carboxamide, NSC- 286193) is a synthetic nucleoside analog with potent antitumor activity. Isolated choroid plexuses (CP) of sheep were perfused in situ and the uptake of [ 3 H]-tiazofurin was determined in relation to the recovery of [ 14 C]- mannitol by means of the paired indicator dilution technique. The maximal uptake of tiazofurin was 8.29 ± 0.84% and was shown to be both carrier- mediated, sodium-dependent and inhibited by adenosine which suggests that it uses the carrier for endogenous nucleosides. However, the total tiazofurin uptake into the choroid plexus was negligible (0.93 ± 1.97%) as a result of a high backflux, indicating that tiazofurin is not trapped within the cells of the CP to any significant degree. The kinetics for the uptake into the CP were more favorable than for its passage across the blood-brain barrier with a K(m) 7.71 ± 1.42 μM, a V(max) of 1.30 ± 0.05 μM/min/g and a negligible constant of a free diffusion (K(2)) which suggests that the CP/CSF route may act as an alternative pathway into the brain. (C) 2000 Prous Science.

Tiazofurin (TZF- beta-D-ribofuranosyl thiazole-4-carboxamide, NSC- 286193) is a synthetic nucleoside analog with potent antitumor activity. Isolated choroid plexuses (CP) of sheep were perfused in situ and the uptake of [ 3 H]-tiazofurin was determined in relation to the recovery of [ 14 C]- mannitol by means of the paired indicator dilution technique. The maximal uptake of tiazofurin was 8.29 ± 0.84% and was shown to be both carrier- mediated, sodium-dependent and inhibited by adenosine which suggests that it uses the carrier for endogenous nucleosides. However, the total tiazofurin uptake into the choroid plexus was negligible (0.93 ± 1.97%) as a result of a high backflux, indicating that tiazofurin is not trapped within the cells of the CP to any significant degree. The kinetics for the uptake into the CP were more favorable than for its passage across the blood-brain barrier with a K(m) 7.71 ± 1.42 μM, a V(max) of 1.30 ± 0.05 μM/min/g and a negligible constant of a free diffusion (K(2)) which suggests that the CP/CSF route may act as an alternative pathway into the brain. (C) 2000 Prous Science.