E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo

Ozawa, Yoichi; Sugi, Naoko Hata; Nagasu, Takeshi; Owa, Takashi; Watanabe, Tatsuo; Koyanagi, Nozomu; Yoshino, Hiroshi; Kitoh, Kyosuke; Yoshimatsu, Kentaro

doi:10.1016/s0959-8049(01)00275-1

Cited by 116 publications

(84 citation statements)

References 18 publications

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“…ABT-751 is a sulphonamide molecule that can be given orally, and has shown significant antitumour activity in a variety of tumour models (Ozawa et al, 2001). In a phase-I study, 39 patients with solid tumours were given ABT-751 once or twice daily for 7 days every 3 weeks (Table 1) (Hande et al, 2006).…”

Section: Abt-751mentioning

confidence: 99%

Vascular disrupting agents in clinical development

2007

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Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

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Section: Abt-751mentioning

confidence: 99%

Vascular disrupting agents in clinical development

2007

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“…CDK inhibitors have the potential to induce cell cycle arrest and apoptosis in tumour cells. Indisulam is a chloro-indoyl sulphonamide anticancer agent that inhibits the phosphorylation of CDK2 and decreases the expression of cyclin E (Ozawa et al, 2001). This is accompanied by hypophosphorylation of the retinoblastoma protein.…”

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confidence: 99%

“…Indisulam also reduces the expression of cyclins A, B1 and H. This ultimately results in cell cycle arrest at multiple checkpoints. At higher concentrations, treatment with indisulam was associated with upregulation of p53 and p21 resulting in apoptotic cell death (Fukuoka et al, 2001;Ozawa et al, 2001).…”

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confidence: 99%

A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

et al. 2008

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This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1 -14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m À2 and capecitabine 1250 mg m À2 BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m À2 and capecitabine 1250 mg m À2 BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug -drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m À2 ) in combination with capecitabine (1250 mg m À2 BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m À2 and capecitabine 1250 mg m À2 BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug -drug interaction.

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“…E7070 is a chloroindolyl sulphonamide that induces G1/S cell cycle arrest at low nanomolar concentrations, inhibiting Cdk2/cyclin E, downregulating cyclin H, upregulating p53 and p21, and inducing (Ozawa et al, 2001). Its potency is enhanced by longer drug exposures (Ozawa et al, 2001).…”

Section: E7070mentioning

confidence: 99%

“…Its potency is enhanced by longer drug exposures (Ozawa et al, 2001). E7070 has a broad spectrum of in vitro and in vivo preclinical antitumour activity, inducing regression of established tumours.…”

Section: E7070mentioning

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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E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo

Cited by 116 publications

References 18 publications

Vascular disrupting agents in clinical development

Vascular disrupting agents in clinical development

A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

Clinical anticancer drug development: targeting the cyclin-dependent kinases

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