Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms

Sausville, Edward A.; Arbuck, Susan G.; Messmann, Richard A.; Headlee, Donna; Bauer, Kenneth S.; Lush, Richard M.; Murgo, Anthony J.; Figg, William D.; Lahusen, Tyler; Jaken, Susan; Jing, Xiu-xian; Roberge, Michel; Fuse, Eiichi; Kuwabara, Takashi; Senderowicz, Adrian M.

doi:10.1200/jco.2001.19.8.2319

Cited by 293 publications

(209 citation statements)

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“…In summary, UCN-01 and VA, at clinically achievable drug concentrations and conditions (for instance 1.0 mM of VA and 500 nM of UCN-01) (Brodie and Dichter, 1996;Sausville et al, 2001), interact to mediate additive and supra-additive induction of apoptosis of cultured thoracic cancer cells. This chemosensitisation effect of UCN-0-1 in VA-treated cells is most likely secondary to its effect on downregulation of essential signal transduction pathways (PKC, ERK1/2, NF-kB) that regulate HDACI-induced apoptosis.…”

Section: Discussionmentioning

confidence: 97%

“…Exposure of cultured cancer cells to UCN-01 (250 -1000 nM) resulted in complete abrogation of phosphorylation at Ser473 and Thr308 residues of Akt, both of which are essential for full activation of Akt kinase activity (Amornphimoltham et al, 2004;Kondapaka et al, 2004). Clinical trials of UCN-01 in patients with refractory neoplasms, as monotherapy or in combination with cytotoxic chemotherapeutics, have been reported (Sausville et al, 2001). Continuous 72-h infusion of UCN-01 resulted in 'free' (after ultracentrifugation) plasma drug concentrations of 200 -600 nM and tissue drug concentration (via measurement of salivary UCN-01 concentrations as surrogates) of 110 nM (Sausville et al, 2001).…”

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confidence: 99%

“…Clinical trials of UCN-01 in patients with refractory neoplasms, as monotherapy or in combination with cytotoxic chemotherapeutics, have been reported (Sausville et al, 2001). Continuous 72-h infusion of UCN-01 resulted in 'free' (after ultracentrifugation) plasma drug concentrations of 200 -600 nM and tissue drug concentration (via measurement of salivary UCN-01 concentrations as surrogates) of 110 nM (Sausville et al, 2001). In view of the facts that STP and its clinically relevant analogue UCN-01 inhibit multiple kinases known to influence the cytotoxic effect of HDACIs in cancer cells, we hypothesised that STP or UCN-01 would synergise with HDACIs to promote profound induction of apoptosis.…”

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confidence: 99%

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Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

et al. 2006

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Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-kB inhibitor) abrogates HDACI-induced transcriptional activation of NF-kB and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62 -10.0 mM) resulted in significant cell line-and dose-dependent growth inhibition (IC 50 values: 4.1 -6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5 -20-fold upregulation of transcriptional activity of NF-kB was substantially (50 -90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (o20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60 -90% of cells underwent apoptosis following exposure to combinations of VA þ kinase inhibitors. Kinase inhibitor-mediated suppression of NF-kB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kB by Parthenolide drastically synergised with VA to induce apoptosis (VA þ Parthenolide: 60 -90% compared to o20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-kB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

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confidence: 99%

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Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

et al. 2006

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“…The phase I clinical trial did show evidence of activity in lymphomas, 28 with similar evidence reported in chronic lymphocytic leukemia (CLL) patients treated with a UCN-01 and fludarabine combination. 29 Depsipeptide derived from Chromobacterium violaceum, causes down-regulation of cyclin D1, up-regulation of cyclin E and p21-dependent cell cycle arrest at G 1 and G 2 .…”

Section: Spotlightmentioning

confidence: 62%

Developmental Therapeutics Program at the NCI: molecular target and drug discovery process

2002

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As the drug discovery and developmental arm of the National Cancer Institute (NCI), the Developmental Therapeutics Program (DTP) plans, conducts and facilitates development of therapeutic agents for cancer and AIDS. DTP's goal is to turn 'molecules into medicine for the public health'. Areas of support by DTP are discovery, development and pathways to development for the intramural and the extramural community.

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“…Frequent dosing is required to optimise the antitumour activity of UCN-01 , and 72 h of drug exposure is required to achieve growth inhibition. A Phase I trial of UCN-01 administered as a 72-h continuous infusion every 2 weeks to patients with advanced malignancy revealed long elimination half-lives due to high-affinity binding of UCN-01 to a1-acid glycoprotein in human plasma Sausville et al, 2001). This schedule was therefore changed to a 72-h continuous infusion administered every 4 weeks, with a recommended dose of 42.5 mg m 2 day À1 .…”

Section: Ucn-01mentioning

confidence: 99%

Clinical anticancer drug development: targeting the cyclin-dependent kinases

et al. 2004

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Cell division involves a cyclical biochemical process composed of several step-wise reactions that have to occur once per cell cycle. Dysregulation of cell division is a hallmark of all cancers. Genetic and epigenetic mechanisms frequently result in deranged expression and/or activity of cell-cycle proteins including the cyclins, cyclin-dependent kinases (Cdks), Cdk inhibitors and checkpoint control proteins. The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity.

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Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms

Abstract: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

Cited by 293 publications

References 17 publications

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Developmental Therapeutics Program at the NCI: molecular target and drug discovery process

Clinical anticancer drug development: targeting the cyclin-dependent kinases

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