Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(4-(Tetrahydro-2H-pyran-2-yloxy)R1)R2-diamminedichloroplatinum(II) complexes (1-12) consisting of CDDP linked to THP via aliphatic CH2-spacers were tested in two TGCT cell lines. The most promising compound, 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II) (12), completely overcame CDDP resistance of 1411HP cells, correlating with increased and accelerated cellular platinum uptake and much faster initiation of apoptotic cell kill. At equitoxic IC90 concentrations, 12 induced accelerated DNA fragmentation and caspase -3 and PARP cleavages. In contrast, DNA platination rate was much lower as compared to CDDP and no upregulation of p53 as well as no initiation of cell cycle arrest were observed. Apoptosis induction by 12 could not be inhibited by pretreatment with caspase-specific inhibitor Z-VAD-Fmk and was accompanied by strong calcium release and generation of reactive oxygen species. To summarize, 12 overcomes CDDP resistance and induces programmed cell death with molecular features different from CDDP, suggesting that both drugs induce apoptosis through different initial pathways.
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PMID:2-(4-(Tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II): a novel platinum compound that overcomes cisplatin resistance and induces apoptosis by mechanisms different from that of cisplatin. 1869 54

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.
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PMID:Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review. 2782 2