Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sensitivity of three Lewis lung carcinoma sublines, which grow in culture and in vivo, and vary in in vivo drug sensitivity, have been compared using topoisomerase II poisons amsacrine, amsacrine analogue CI-921, doxorubicin and etoposide. D10 (drug concentration for 10% clonogenic survival) values were determined in vitro for low and high density cultures, and ex vivo for cells from subcutaneous tumours. The cytokinetic parameters of these populations were obtained by flow cytometric analysis of bromodeoxyuridine-labelled cells. Regression analysis showed that logarithmic D10 values were significantly correlated (r greater than 0.95) with G1- and S-phase proportions and highly correlated (r = 0.99) with calculated G1 transit times. The slopes of the regression lines were similar for all topoisomerase II poisons tested and it is suggested that this slope reflects the disappearance of topoisomerase II during G1 phase.
 ...
PMID:Relationship of cell cycle parameters to in vitro and in vivo chemosensitivity for a series of Lewis lung carcinoma lines. 151 64

Topotecan (SK&F 104864), a water-soluble analogue of the topoisomerase I inhibitor camptothecin, is currently in Phase II clinical trial for solid tumors. We have characterized topotecan in terms of its effect upon gamma-radiation-induced cell killing. In colony formation experiments, subtoxic concentrations of topotecan (2 microM) potentiated radiation-induced killing of exponentially growing Chinese hamster ovary or P388 murine leukemia cultured cells. Survival curve shoulders were reduced; the slopes of the exponential portions of the curves were decreased to a small extent. D37 and D10 (radiation dose resulting in 37 and 10% survival of colony-forming ability) values were reduced by approximately 60 and 50%, respectively, in the case of Chinese hamster ovary cells. In P388 cells, topotecan reduced D37 by 35 to 40% and D10 by 20 to 25%. Potentiation of radiation-induced cell killing by topotecan was absolutely dependent upon the presence of the topoisomerase I inhibitor during the first few (less than 30) min after irradiation. Association of topoisomerase I with this effect was confirmed in studies of Chinese hamster ovary cells previously made resistant to camptothecin (and cross-resistant to topotecan), resulting in decreased cellular content of topoisomerase I. These cells were found to be 2- to 3-fold hypersensitive to gamma-radiation-induced killing. P388 camptothecin-resistant cells were further sensitized to the lethal effects of ionizing radiation by nontoxic treatment with the topoisomerase II inhibitor novobiocin, consistent with increased dependence of topoisomerase I-deficient cells upon topoisomerase II.
 ...
PMID:Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). 165 71

A spontaneous derivative of murine L tk- cells has been isolated which has gained a resistance to the cytostatic/lethal effects of high concentrations of Hoechst 33258. The resistant clone HoeR-415 was at least 20-fold more resistant to the dye (D10 dose). HoeR-415 cells have a normal response to X-rays and mitomycin-C and colchicine but were found to show a small sensitivity to UV light, 4NQO, and EMS (1.4, 1.6, and 1.6-fold lower D10 doses, respectively). HoeR-415 cells do not show an increased mutability by EMS. The HoeR phenotype was found to be codominant in hybrids. In order to explain these various characteristics, we suggest that the HoeR-415 mutation may result in an altered topoisomerase activity. Consistent with this we find HoeR-415 cells have an increased sensitivity to novobiocin.
 ...
PMID:Dominant mutation in mouse cells associated with resistance to Hoechst 33258 dye, but sensitivity to ultraviolet light and DNA base-damaging compounds. 243 73

We have compared the effects of a number of inhibitors including aphidicolin, 2,4-dinitrophenol (DNP) and novobiocin on the in vitro cytotoxicity of several topoisomerase II (topo II)-directed agents, using cultured murine Lewis lung carcinoma cells. These agents comprised amsacrine, CI-921 (9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-N,5-dimethyl-4- acridinecarboxamide isethionate, isethionate, a derivative of amsacrine), DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride, a new DNA intercalator with high solid tumor activity), daunorubicin, doxorubicin, epirubicin, etoposide, mitoxantrone, and teniposide. Novobiocin, an antibiotic that affects topo II action, reduced the cytotoxic effect of DACA as well as that of amsacrine and doxorubicin, and reduced the extent of G2-phase arrest by DACA. DNP, an uncoupler of mitochondrial respiration, inhibited drug action in a manner similar to that of novobiocin but to a smaller extent. Aphidicolin, a specific inhibitor of DNA polymerase-alpha, reduced the cytotoxic effect of amsacrine, CI-921, etoposide, and teniposide but not that of DACA, daunorubicin, doxorubicin, epirubicin, or mitoxantrone. The immediate effect of each topo II-directed agent on the incorporation of thymidine into DNA was also measured at a drug concentration (D10) that killed 90% of cells. Susceptibility to aphidicolin reversal was strongly correlated with inhibition of thymidine incorporation (r = 0.91; p < or = 0.001). The results suggest that the involvement of DNA replication in the cytotoxic action of topo II-directed agents differs according to the agent used.
 ...
PMID:A comparison of the effects of aphidicolin and other inhibitors on topoisomerase II-directed cytotoxic drugs. 826 Jul 50