Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.64 (proteinase K)
 4,071 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation and repair of cis-diamminedichloroplatinum(II) (cis-DDP)-induced DNA cross-links in cells from a number of different mouse tissues, both normal and neoplastic, were compared in three different populations of animals, tumor-free mice and mice bearing a transplanted fibrosarcoma (either FSa or NFSa) in their thighs. Groups of mice were given i.v. injections of 4-12-mg/kg doses of cis-DDP, and the amount of cis-DDP-induced DNA cross-linking was determined at different times after injection using an adaptation of the alkaline elution technique. The degree of cross-linking in each tissue was linearly related to the dose of cis-DDP at either 6 or 24 h after injection and varied significantly among the different tissues, with FSa, NFSa, kidney, and liver showing the highest level of cross-linking of the tissues studied. The relative contributions of DNA-interstrand and DNA-protein cross-links to the elution profiles were estimated by proteinase K (PK) digestion. At either 6 or 24 h after injection with cis-DDP, the rate of elution of the DNA was substantially increased by PK, indicating a large contribution of DNA-protein cross-links. This effect was observed in all tissues studied, although the proportion of PK-resistant lesions appeared to vary from tissue to tissue, liver and spleen showing a significantly lower proportion of DNA-interstrand to total cross-links than either of the tumors. For liver, virtually no interstrand cross-links could be detected after PK treatment. The kinetics of the repair of cis-DDP-induced DNA cross-linking in these tissues were also compared. In cells from tumor-free animals, the amount of total (DNA-interstrand plus DNA-protein) cross-linking increased gradually, reaching a maximum after about 6 h; however, little evidence of repair of these lesions was observed in any of these normal tissues. In fact, the degree of cross-linking tended to increase somewhat between 6 and 24 h after injection. The kinetics of cross-linking in cells isolated from the FSa tumor were very different; while there was an initial increase in cross-linking up to 6 h, these lesions were subsequently repaired, although at a somewhat slower rate than has been reported for cultured mammalian cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Kinetics of DNA cross-linking in normal and neoplastic mouse tissues following treatment with cis-diamminedichloroplatinum(II) in vivo. 406 92

The dynamic development of metal-containing anticancer drugs has started since the discovery of cis-diamminedichloroplatinum(II). For many years it was believed that trans platinum(II) compounds were non-active as antitumour agents because trans-diamminedichloroplatinum is biologically inactive although it binds to DNA and also forms monoadducts and cross-links. In the present work the ability of a novel platinum(II) compound trans-[PtCl(2)(4-pmOpe)(2)] to induce DNA damage in human non-small cell lung cancer cells A549 was examined using the alkaline comet assay. The obtained results revealed that the novel trans platinum(II) complex induced DNA strand breaks, which were effectively repaired during 2h of post-incubation, and cross-links which remained unrepaired under these test conditions. Apart from that, the modified comet assay with incubation with proteinase K was used to verify the ability of trans-[PtCl(2)(4-pmOpe)(2)] and cis-DDP to form DNA-protein cross-links. It has been proved that only trans-[PtCl(2)(4-pmOpe)(2)] complex exhibits the ability to induce DNA-protein cross-links. The results suggest a different mechanism of action of this compound in comparison to cis-DDP. It seems that trans geometry and the presence of two diethyl (pyridin-4-ylmethyl)phosphates as non-leaving ligands can determine dissimilar properties of the adducts formed on DNA and the different mechanism of action of trans-[PtCl(2)(4-pmOpe)(2)] and in consequence the efficacy in killing cancer cells.
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PMID:Genotoxicity of novel trans-platinum(II) complex with diethyl (pyridin-4-ylmethyl)phosphate in human non-small cell lung cancer cells A549. 1749 50