Preclinical pharmacokinetics and in vitro activity of ON 01910.Na, a novel anti-cancer agent

Chun, Amy W.; Cosenza, Stephen C.; Taft, David R.; Maniar, Manoj

doi:10.1007/s00280-009-1022-9

Cited by 28 publications

(21 citation statements)

References 8 publications

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“…It shows significant in vitro activity against mantle cell lymphoma lines which over-express cyclin D1, decreases c-myc and cyclin D1 levels, and stimulates apoptosis through release of caspases and modulation of Bcl-2. Animal studies using ON 01910.Na show little toxicity, and this compound is well-tolerated in phase I studies of patients solid tumors [17,18]. We examined the effects of ON 01910.Na on MDS cells in vitro , and report the results of a phase I clinical trial treating patients with high risk MDS and trisomy 8 AML.…”

Section: Introductionmentioning

confidence: 99%

Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na

et al. 2012

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Background We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). “Knockdown” of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS. Experimental Design We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON01910.Na on a phase I clinical protocol (NCT00533416). Results ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON01910.Na on a clinical had decreased bone marrow blasts by ≥50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells. Conclusions The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients.

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Section: Introductionmentioning

confidence: 99%

Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na

et al. 2012

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“…Analysis of ON01910 in animal and human plasma using LC/MS/MS has been reported [2, 3] based on sample sizes of 0.1 ml although for our studies, a sample size of 10 μl was the limit and a key consideration in the development of the assay. In addition, the LC/MS/MS method had to be applicable to normal brain and brain tumor, the latter being the intended site of action, which had not been previously investigated.…”

Section: Introductionmentioning

confidence: 93%

Application of a liquid chromatography–tandem mass spectrometry (LC/MS/MS) method to the pharmacokinetics of ON01910 in brain tumor-bearing mice

Nuthalapati

Guo

Zhou

et al. 2011

Journal of Pharmaceutical and Biomedical Analysis

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ON01910 is a small molecular weight benzyl styryl sulfone currently under investigation as a novel anticancer agent. The purpose of the investigation was to develop a sensitive and reproducible liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to quantitate levels of ON01910 in small amounts of five biological matrices; mouse plasma, feces, urine, normal brain and brain tumor. For all matrices, protein precipitation sample preparation was used that led to linear calibration curves with coefficients of determination greater than 0.99. The lower limit of quantitation (LLOQ) for all matrices was 5 ng/ml except that for mouse urine which was 10 ng/ml. The calibration standard curves were reproducible for all matrices with inter- and intra-day variability in precision and accuracy being less than 15% at all quality control concentrations except for the LLOQ in mouse plasma for which the accuracy was within 17%. The assay was successfully applied to characterize the systemic pharmacokinetics of ON01910 as well as its disposition in brain and brain tumor in mice. ON01910 exhibited a clearance of 3.61 ± 0.85 l/hr/Kg and a half life of 8.66 ± 3.30 hrs at 50 mg/kg dose given I.V.

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“…It has been shown to inhibit PLK1 pathway activity at a nanomolar range in a substrate-dependent and ATP-independent manner, although targeting other kinases has also been reported. 1 , 2 This compound inhibits a broad spectrum of human tumour cells growth with GI 50 values in the nanomolar range and is active in a number of human xenografts in mice 3,4 . Currently, the drug is in several phase I and II clinical trials in adult patients with a variety of solid tumours as well as hematological malignancies.…”

Section: Sodiummentioning

confidence: 99%

Synthesis and biological evaluation of benzyl styrylsulfonyl derivatives as potent anticancer mitotic inhibitors

Chahrour

Abdalla

Lam

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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Preclinical pharmacokinetics and in vitro activity of ON 01910.Na, a novel anti-cancer agent

Abstract: Due to the short half-life and rapid clearance of the drug, administration of ON 01910.Na by continuous IV infusion is a likely treatment option for cancer patients.

Cited by 28 publications

References 8 publications

Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na

Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na

Application of a liquid chromatography–tandem mass spectrometry (LC/MS/MS) method to the pharmacokinetics of ON01910 in brain tumor-bearing mice

Synthesis and biological evaluation of benzyl styrylsulfonyl derivatives as potent anticancer mitotic inhibitors

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