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)

Amplification of cellular proto-oncogenes has been implicated in the development of human malignancies. A library was constructed from genomic DNA extracted from a lung tumour, previously shown to carry an amplified c-Ki-ras 2 gene. Using a v-Ki-ras probe, a fragment with ras homology was isolated and shown to be amplified in the original tumour DNA to the same level as c-Ki-ras. Studies with human hamster hybrids demonstrated that it is normally located on human chromosome 12 (as is c-Ki-ras). The restriction map of the fragment is different from that of the known Ha, Ki or N-ras genes and its sequence shows evolutionary conservation, as demonstrated by hybridisation to the genomic DNA of several mammalian species. A pUC19 subclone (pK42), carrying a 1.3kb insert, shows supercoil heterogeneity in plasmid preparations, as does a second compatible plasmid introduced into the same bacterial host with pK42. It appears therefore that the subclone is encoding a product that affects DNA topoisomerase activity in E. coli.
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PMID:Isolation of a human genomic fragment, co-amplified with c-Ki-ras, that affects plasmid supercoiling in E. coli. 303 3

We used human tumor cell lines from the National Cancer Institute's In Vitro Antineoplastic Drug Screen to assess whether sensitivity to any of the approximately 45,000 compounds tested previously correlated with the presence of a ras oncogene. Among these cell lines, the mutations in Ki-ras2 clustered in non-small cell lung and colon carcinoma subpanels, and five of the six leukemia lines contained mutations in either N-ras or Ki-ras2. These analyses revealed a striking correlation with 1-beta-D-arabinofuranosylcytosine (Ara-C) and 2,2'-O-cyclocytidine sensitivity in the cell lines harboring ras mutations compared to the tumor lines with wild-type ras alleles. Strong correlations were also found with topoisomerase (topo) II inhibitors, especially 3'-hydroxydaunorubicin and an olivacine derivative. These differential sensitivities persisted in an additional 22 non-small cell lung carcinoma lines (ras mutations, n = 12 and wild-type ras, n = 10). Thus, the association with Ara-C sensitivity was greatest while topo II inhibitors showed a lower, but significant, correlation. These results suggest that the ras oncogene may play a determinant role in rendering tumor cells sensitive to deoxycytidine analogues and topo II inhibitors.
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PMID:Enhanced sensitivity to 1-beta-D-arabinofuranosylcytosine and topoisomerase II inhibitors in tumor cell lines harboring activated ras oncogenes. 891 59