A phase II trial of Triapine® (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503

Traynor, Anne M.; Lee, Ju Whei; Bayer, Gerald K.; Tate, John M.; Thomas, Sachdev; Mazurczak, Miroslaw; Graham, David L.; Kolesar, Jill; Schiller, Joan H.

doi:10.1007/s10637-009-9230-z

Cited by 105 publications

(104 citation statements)

References 25 publications

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“…In contrast, prior to our study other phase I/II trials of this combination with different dose/ schedule [32,[42][43][44], reported more significant toxicities including hypoxia, methemoglobinemia and significant cardiopulmonary toxicity. The initial phase I trial defined the MTD as triapine at 105 mg/m 2 infused over 2-4 h followed by gemcitabine at 1000 mg/m 2 over 30 min (standard-dose), on days 1, 8, and 15, for a 28-day cycle [32].…”

Section: Discussioncontrasting

confidence: 59%

“…The initial phase I trial defined the MTD as triapine at 105 mg/m 2 infused over 2-4 h followed by gemcitabine at 1000 mg/m 2 over 30 min (standard-dose), on days 1, 8, and 15, for a 28-day cycle [32]. This recommended phase II dose was tested in 4 different phase II solid tumor trials including 2 in non-small cell lung cancer, 1 in advanced pancreas cancer and 1 in biliary cancer [42][43][44][45]. Taken together, the only observed responses were in 3 patients with biliary cancers.…”

Section: Discussionmentioning

confidence: 99%

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A phase I study of prolonged infusion of triapine in combination with a fixed-dose rate of gemcitabine in patients with advanced solid tumors.

Mortazavi¹,

Deam²,

Ling³

et al. 2010

JCO

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

A phase I study of prolonged infusion of triapine in combination with a fixed-dose rate of gemcitabine in patients with advanced solid tumors.

Mortazavi¹,

Deam²,

Ling³

et al. 2010

JCO

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“…However, other studies suggest some positive results after 3-AP was coadministered with cisplatin and daily pelvic radiation in patients with locally advanced cervical and vaginal cancer (Kunos et al, 2010). The notable side effects of 3-AP include hypoxia and methemoglobinemia (Yen et al, 2004;Gojo et al, 2007;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010), which are major concerns for patients with compromised cardiopulmonary function.…”

Section: Introductionmentioning

confidence: 99%

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

Quach¹,

Gutierrez²,

Basha³

et al. 2012

Mol Pharmacol

103

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Thiosemicarbazones are a group of compounds that have received comprehensive investigation as anticancer agents. The antitumor activity of the thiosemicarbazone, 3-amino-2-pyridinecarboxaldehyde thiosemicarbazone (3-AP; triapine), has been extensively assessed in more than 20 phase I and II clinical trials. These studies have demonstrated that 3-AP induces methemoglobin (metHb) formation and hypoxia in patients, limiting its usefulness. Considering this problem, we assessed the mechanism of metHb formation by 3-AP compared with that of more recently developed thiosemicarbazones, including di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). This was investigated using intact red blood cells (RBCs), RBC lysates, purified oxyhemoglobin, and a mouse model. The chelation of cellular labile iron with the formation of a redox-active thiosemicarbazone-iron complex was found to be crucial for oxyhemoglobin oxidation. This observation was substantiated using a thiosemicarbazone that cannot ligate iron and also by using the chelator, desferrioxamine, that forms a redox-inactive iron complex. Of significance, cellular copper chelation was not important for metHb generation in contrast to its role in preventing tumor cell proliferation. Administration of Dp44mT to mice catalyzed metHb and cardiac metmyoglobin formation. However, ascorbic acid administered together with the drug in vivo significantly decreased metHb levels, providing a potential therapeutic intervention. Moreover, we demonstrated that the structure of the thiosemicarbazone is of importance in terms of metHb generation, because the DpT analog, di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), does not induce metHb generation in vivo. Hence, DpC represents a next-generation thiosemicarbazone that possesses markedly superior properties. This investigation is important for developing more effective thiosemicarbazone treatment regimens.

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“…1A) belongs to the large class of a-Nheterocyclic thiosemicarbazones. Its antitumor activity has been known for more than a decade and was studied in several clinical phase I and phase II trials (Nutting et al, 2009;Kunos et al, 2010;Traynor et al, 2010;Ocean et al, 2011). The anticancer activity of 3-AP has been attributed to the inhibition of the ribonucleotide reductase enzyme (Finch et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

et al. 2013

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Triapine (3-AP; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a ribonucleotide reductase inhibitor, has been extensively evaluated in clinical trials in the last decade. This study addresses the role of endoplasmic reticulum (ER) stress in the anticancer activity of 3-AP and the derivative N 4 ,N 4 -dimethyltriapine (3-AP-Me), differing from 3-AP only by dimethylation of the terminal nitrogen. Treatment of colon cancer cells with 3-AP or 3-AP-Me activated all three ER stress pathways (PERK, IRE1a, ATF6) by phosphorylation of eIF2a and upregulation of gene expression of activating transcription factors ATF4 and ATF6. In particular, 3-AP-Me led to an upregulation of the alternatively spliced mRNA variant XBP1 (16-fold). Moreover, 3-AP and 3-AP-Me activated the cellular stress kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, and inhibition of JNK activity antagonized the cytotoxic effect of both compounds. Subsequent to induction of the unfolded protein response, a significant upregulation of proapoptotic proteins was detected, including the transcription factor CHOP and Bim, an essential factor for ER stress-related apoptosis. In correlation with the higher degree of ER stress after 3-AP-Me treatment, also a more potent depolarization of mitochondrial membranes was found. These data suggest that 3-AP and 3-AP-Me induce apoptosis via ER stress. This was further corroborated by showing that inhibition of protein biosynthesis with cycloheximide prior to 3-AP and 3-AP-Me treatment leads to a significant reduction of the antiproliferative properties of both compounds. Taken together, this study demonstrates that induction of ER stress contributes to the mode of action of 3-AP and that terminal dimethylation leads to an even more pronounced manifestation of this effect.

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A phase II trial of Triapine® (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503

Abstract: SummaryBackground-The objective of ECOG 1503 was to determine the response rate of this combination in the second-line treatment of advanced NSCLC.

Cited by 105 publications

References 25 publications

A phase I study of prolonged infusion of triapine in combination with a fixed-dose rate of gemcitabine in patients with advanced solid tumors.

A phase I study of prolonged infusion of triapine in combination with a fixed-dose rate of gemcitabine in patients with advanced solid tumors.

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

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