A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

Kolesar, Jill; Mahoney, Michelle R.; Pitot, Henry C.; Laheru, Daniel A.; Heun, James M.; Huang, Wei; Eickhoff, Jens; Erlichman, Charles; Holen, Kyle D.

doi:10.1007/s10637-008-9123-6

Cited by 77 publications

(66 citation statements)

References 39 publications

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“…For example, the short half-life, low membrane permeability, and lack of activity following oral administration of desferrioxamine have limited its antitumor activity in clinical settings (18). Recently, triapine, a tridentate iron chelator, produced doselimiting toxicities in phase II trials in patients with non-small-cell lung and prostrate cancer without clear therapeutic benefit (36,37). The hexadentate iron chelator tachypyridine, by arresting cancer cells in the G 2 phase of the cell cycle, showed antitumor and radiation-sensitizing activity that remains to be extended to the clinic (11).…”

Section: Discussionmentioning

confidence: 99%

The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells

et al. 2009

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Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is being developed as an iron chelator with selective anticancer activity. We investigated the mechanism whereby Dp44mT kills breast cancer cells, both as a single agent and in combination with doxorubicin. Dp44mT alone induced selective cell killing in the breast cancer cell line MDA-MB-231 when compared with healthy mammary epithelial cells (MCF-12A). It induces G 1 cell cycle arrest and reduces cancer cell clonogenic growth at nanomolar concentrations. Dp44mT, but not the iron chelator desferal, induces DNA double-strand breaks quantified as S139 phosphorylated histone foci (;-H2AX) and Comet tails induced in MDA-MB-231 cells. Doxorubicin-induced cytotoxicity and DNA damage were both enhanced significantly in the presence of low concentrations of Dp44mT. The chelator caused selective poisoning of DNA topoisomerase IIA (top2A) as measured by an in vitro DNA cleavage assay and cellular topoisomerase-DNA complex formation. Heterozygous Nalm-6 top2A knockout cells (top2A +/À ) were partially resistant to Dp44mT-induced cytotoxicity compared with isogenic top2A +/+ or top2B À/À cells.Specificity for top2A was confirmed using top2A and top2B small interfering RNA knockdown in HeLa cells. The results show that Dp44mT is cytotoxic to breast cancer cells, at least in part, due to selective inhibition of top2A. Thus, Dp44mT may serve as a mechanistically unique treatment for cancer due to its dual ability to chelate iron and inhibit top2A activity.

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Section: Discussionmentioning

confidence: 99%

The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells

et al. 2009

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“…It is notable that the thiosemicarbazone 3-AP has already been through clinical trials for the treatment of a range of tumors including pancreatic cancer (Attia et al, 2008). In fact, phase II clinical trials were performed using 3-AP in combination with gemcitabine, because these drugs were observed to have synergistic effects (Mackenzie et al, 2007).…”

Section: Cip1/waf1mentioning

confidence: 99%

“…In fact, phase II clinical trials were performed using 3-AP in combination with gemcitabine, because these drugs were observed to have synergistic effects (Mackenzie et al, 2007). However, these studies found that 3-AP induced significant toxicity with little therapeutic benefit (Mackenzie et al, 2007;Attia et al, 2008). Considering that Dp44mT is far more potent and less toxic than 3-AP (Yuan et al, 2004;Whitnall et al, 2006), both Dp44mT and DpC are new and more effective alternatives to this agent.…”

Section: Cip1/waf1mentioning

confidence: 99%

Novel Thiosemicarbazone Iron Chelators Induce Up-Regulation and Phosphorylation of the Metastasis Suppressor N-myc Down-Stream Regulated Gene 1: A New Strategy for the Treatment of Pancreatic Cancer

et al. 2011

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Pancreatic cancer is an aggressive neoplasm, with a mortality rate close to 100%. The most successful agent for pancreatic cancer treatment is gemcitabine, although the overall effect in terms of patient survival remains very poor. This study was initiated to evaluate a novel class of anticancer agents against pancreatic cancer. This group of compounds belongs to the dipyridyl thiosemicarbazone class that have been shown to have potent and selective activity against a range of different neoplasms in vitro and in vivo. We demonstrate for the first time in pancreatic cancer that these agents increase the expression of the growth and metastasis suppressor N-myc downstreamregulated gene 1 and its phosphorylation at Ser330 and Thr346 that is important for its activity against this tumor. In addition, these agents increased expression of the cyclin-dependent kinase inhibitor p21 CIP1/WAF1 , whereas decreasing cyclin D1 in pancreatic cancer cells. Together, these molecular alterations account, in part, for the pronounced antitumor activity observed. Indeed, these agents had significantly higher antiproliferative activity in vitro than the established treatments for pancreatic cancer, namely gemcitabine and 5-fluorouracil. Studies in vivo demonstrated that a novel thiosemicarbazone, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride, completely inhibited the growth of pancreatic cancer xenografts with no evidence of marked alterations in normal tissue histology. Together, our studies have identified molecular effectors of a novel and potent antitumor agent that could be useful for pancreatic cancer treatment.

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“…13 However, other clinical phase II studies showed that Triapine is ineffective against a variety of solid tumors including pancreatic, adeno-, lung and renal carcinoma. 14,15,16,17 In the 1970s it was discovered that HCTs are inhibitors of the enzyme ribonucleotide reductase (RNR), 18,19 which catalyzes the rate determining step of DNA synthesis, namely the reduction of ribonucleotides to the corresponding 2'-deoxyribonucleotides. 20 Several mechanisms of RNR inhibition by thiosemicarbazones and especially Triapine have been proposed.…”

Section: Introductionmentioning

confidence: 99%

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

et al. 2014

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The nickel(II), copper(II) and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H 2 L 1 ) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazonehave been synthesized and characterized by elemental analysis, one-and two-dimensional 1 H and 13 C NMR spectroscopy, CD, UV−vis and ESI mass spectrometry. Compounds 13, 6 and 7 have been also studied by single crystal X-ray diffraction. Magnetic properties and solid state high-field EPR spectra of 2 over the range 50420 GHz were investigated. The complex formation processes of L-Pro-FTSC with nickel(II) and zinc(II) have been studied in aqueous solution due to the excellent water solubility of the complexes via pH-potentiometry, UV−vis and 1 H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds.3

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A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

Cited by 77 publications

References 39 publications

The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells

The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells

Novel Thiosemicarbazone Iron Chelators Induce Up-Regulation and Phosphorylation of the Metastasis Suppressor N-myc Down-Stream Regulated Gene 1: A New Strategy for the Treatment of Pancreatic Cancer

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

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