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Differential processing of antitumour-active and antitumour-inactive trans platinum compounds by SKOV-3 ovarian cancer cells.

Abstract
In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl(2)(NH(3))(2)] (trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans-Z and trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC(50) determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.
AuthorsAngelina Boccarelli, Domenico Giordano, Giovanni Natile, Mauro Coluccia
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 72 Issue 3 Pg. 280-92 (Jul 28 2006) ISSN: 0006-2952 [Print] England
PMID16765322 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cross-Linking Reagents
  • Organoplatinum Compounds
  • dichlorobis(1-methoxyethanimine)platinum(II)
  • transplatin
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Agents (chemistry, toxicity)
  • Apoptosis (genetics)
  • Cell Cycle (drug effects)
  • Cell Cycle Proteins (genetics)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Cisplatin (chemistry, metabolism, toxicity)
  • Cross-Linking Reagents (chemistry, toxicity)
  • DNA Fragmentation (drug effects)
  • DNA Repair (genetics)
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Genomic Instability (genetics)
  • Inhibitory Concentration 50
  • Organoplatinum Compounds (chemistry, metabolism, toxicity)
  • Ovarian Neoplasms (genetics, metabolism, pathology)
  • Stereoisomerism

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