Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

cis-Diamminedichloroplatinum(II) (cisplatin) forms adducts with DNA. The sequence specificity of formation of cisplatin adducts with plasmid DNA was investigated using Taq DNA polymerase. This procedure involved the extension of an oligonucleotide primer by Taq DNA polymerase up to the cisplatin adduct. Using thermal cycling, this process is repeated many times in order to amplify the signal. The products of this linear amplification can then be examined on DNA sequencing gels, and the sequence specificity of cisplatin adduct formation can be determined to the exact base pair. In the pUC8 plasmid, the sequences that produced the most intense damage sites (as determined by densitometry) were runs of two or more Gs. Adducts could also be detected at GA, AG, and GC dinucleotides. Four other cisplatin analogues were also tested in the system. Two of these analogues contained an attached intercalating chromophore, and the strong damage with these compounds was similar to that found for cisplatin, but the medium and weak damage tended to be different. Weak damage was also detected with trans-diamminedichloroplatinum(II). With this compound, a large number of the damage sites were at the CG dinucleotide. This technique represents a simple, accurate, and quick method for determining the sequence specificity of damage for a cisplatin analogue in any DNA sequence.
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PMID:The use of Taq DNA polymerase to determine the sequence specificity of DNA damage caused by cis-diamminedichloroplatinum(II), acridine-tethered platinum(II) diammine complexes or two analogues. 152 9

cis-Diamminedichloroplatinum(II) (cisplatin; cDDP) derivatives were found to afford T/C% values greater than 200 against the growth of P388 lymphocytic leukemia cells in vivo. The parent compound, cDDP, preferentially inhibited DNA synthesis. The RNA synthesis was elevated, whereas protein synthesis was unaffected after two or three daily ip doses. Radiolabeled drug studies demonstrated cellular uptake and binding of cDDP derivatives to the DNA molecule. cis-Diamminedichloroplatinum(II) (cDDP) treatment resulted in DNA strand scission after a single dose, but caused cross-linking of DNA strands after two or three ip doses. There was an accumulation of deoxynucleoside triphosphates [d(NTP)s] on day 2 and 3, indicating that incorporation of nucleotides into the DNA strand had been blocked. Thymidine kinase, thymidine monophosphate kinase, carbamoyl phosphate synthetase, and aspartate transcarbamoylase activities were inhibited in vivo after three doses of cDDP at 1.5 mg/kg/day. However, only the inhibition of a cytoplasmic preparation of DNA polymerase alpha by cDDP appeared to be directly related to the inhibition of DNA synthesis and the accumulation of d(NTP) pool levels. Thus, the primary target for cDDP appears to be DNA itself, although direct inhibition of DNA polymerase alpha may play a minor role in the inhibition of DNA replication by cDDP.
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PMID:Inhibition of DNA synthesis in P388 lymphocytic leukemia cells of BDF1 mice by cis-diamminedichloroplatinum(II) and its derivatives. 228 Mar 54

Cellular DNA strand break induced by an alkylating agent: Carboquone (CQ), and heat (43 degrees C) was detected in HeLa cells in vitro and mouse sarcoma-180 cells in vivo. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3H]-labeled dTTP and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks increased in a dose and time dependent manner, compared to findings in the control cells. Our findings show that the surviving response of cells decreases while the level of DNA strand breaks increases following exposure to CQ or heat. The nick translation method is a rapid in situ assay for determining drug and heat induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semi-quantitative manner.
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PMID:[Detection of cellular DNA strand breaks induced by antitumor drug and heat using in situ nick translation]. 258 69

cis-Diamminedichloroplatinum (II) (cisplatin) compounds and the chloroethylnitrosoureas are two different classes of anticancer drugs that work by modifying DNA covalently. We have compared the platinating drug cisplatin with the alkylating drug bischloroethylnitrosourea and other chloroethylnitrosoureas by modifying double stranded DNA in vitro and identifying blocking lesions that impede the progress of Escherichia coli DNA polymerase. Despite their very different structures and reactivities, cisplatin and the chloroethylnitrosoureas from primary blocking lesions at identical sequences, those containing adjacent guanosines on the same DNA strand. In tumor virus SV 40 DNA, a very strong target for both types of drugs is the regulatory sequence GGGCGG, which is repeated six times and is an important sequence for viral replication and an essential sequence for expression of the viral transforming gene. Sequences related to these GC box elements are known to be present in the flanking regions of many retroviruses and oncogenes, thus raising the possibility that the targeting of these sequences in tumor cells contributes to drug activity.
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PMID:Formation of blocking lesions at identical DNA sequences by the nitrosourea and platinum classes of anticancer drugs. 304 Feb 38