Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that the multidrug-resistant EHR2/DNR+ cells, which overexpress P-glycoprotein, accumulate only about 20-30% of daunorubicin at steady state compared to the sensitive cells. These cells have been thought to be a "pure" P-glycoprotein cell line. We now report that the EHR2/DNR+ cells exhibit decreased DNA topoisomerase II catalytic activity. We also found that the amount of immunoreactive DNA topoisomerase II from these cells is about one-third that seen in the drug-sensitive cell line. In agreement with the decreased activity and amount of topoisomerase II, the number of DNA-protein complexes stabilized by teniposide (VM-26) was reduced by about 50% in nuclear extracts from EHR2/DNR+ cells. Furthermore, using an intact cell assay for DNA protein complexes, we found that the VM-26-stimulated complexes formed in the drug-resistant cells never reached the level seen in the drug-sensitive cells. Verapamil and Cremophor EL block P-glycoprotein-mediated efflux of "natural product" drugs and increase their accumulation in resistant cells. Coincubation of the EHR2/DNR+ cells with VM-26 and either of these modulators increased the number of complexes formed in the resistant cells. However, neither modulator increased the number of topoisomerase II-DNA complexes in the drug-resistant cells to the level seen in the EHR2 cells. We conclude that the resistance of EHR2/DNR+ cells is due in part to reduced amounts of DNA topoisomerase II. Furthermore, we note that a single cell line can express features of both P-glycoprotein-associated multidrug resistance and altered topoisomerase II-associated multidrug resistance.
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PMID:Decreased DNA topoisomerase II in daunorubicin-resistant Ehrlich ascites tumor cells. 167 12

9-Nitrocamptothecin (9-NC) is an orally administered topoisomerase-I inhibitor for the treatment of pancreatic carcinoma, but its oral absorption and bioavailability are poor. The main objective of this study was to develop optimal 9-nitrocamptothecin (9-NC) microemulsion prepared by self-microemulsifying drug delivery system (SMEDDS). Two SMEDDS formulations of 9-NC prepared from a mixture of ethyl oleate, Tween-80 (T-form) or Cremophor EL (C-form), and PEG-400/ethanol were formed as microemulsions under dilution with aqueous phase. The resulting microemulsions were evaluated in vitro and in vivo, including the kinetics and antitumor effects in SKOV-3 human ovarian cancer xenograft in nude mice. Following 1:10 aqueous dilution of optimal 9-NC SMEDDS, the droplet sizes of resulting microemulsions were (30.8+/-4.6)nm and (39.8+/-8.2)nm for SMEDDS T-form and C-form, respectively, and the zeta potential values were -(4.3+/-0.5)mV and -(5.7+/-0.5)mV, respectively. In SKOV-3 cells, the growth inhibition (IC50) of various 9-NC formulations was greatest with SMEDDS T-form (3.5+/-0.7 nM) followed by SMEDDS C-form (4.6+/-0.4 nM), 9-NC solution (6.6+/-1.4 nM) and 9-NC suspension (26.0+/-2.9 nM) (P<0.01). It was indicated that the area under the plasma concentration-time curve (AUC0-->8h) values of various formulations of 9-NC after oral administration ranked as the following sequence: SMEDDS T-form (360.12+/-19.44 ngh/ml) approximately SMEDDS C-form (351.71+/-33.66 ngh/ml) >9-NC solution (241.21+/-24.67 ngh/ml)>9-NC suspension (161.24+/-24.31 ngh/ml). The 9-NC SMEDDS formulations also produced significantly more tumor shrinkage (P<0.01) when compared to 9-NC suspension in nude mice bearing human ovarian cancer xenografts. The results suggest that SMEDDS is a promising drug delivery system to increase the oral bioavailability and antitumor effects of 9-NC and may be applied to other lipophilic drugs. 9-NC SMEDDS represents a novel 9-NC therapy for cancer patients.
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PMID:Self-microemulsifying drug delivery system (SMEDDS) improves anticancer effect of oral 9-nitrocamptothecin on human cancer xenografts in nude mice. 1843 9