Antitumor Activity and Clinical Pharmacology of Sulofenur in Ovarian Cancer

Taylor, Charles W.; Alberts, David S.; Peng, Yitian; McCloskey, Thomas M.; Matzner, Monika; Roe, Denise J.; Plezia, Patricia M.; Grindey, Gerald B.; Hamilton, Marta; Seitz, David E.

doi:10.1093/jnci/84.23.1798

Cited by 12 publications

(6 citation statements)

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“…El‐Deeb et al evaluated the antitumor effects of some novel cyclic arylsulfonylureas and have shown in a report in 2010 that the tested compounds may have a good inhibitory effect on an ovarian cancer cell line. This finding was compatible with an earlier study by Taylor et al published in 1992. Therefore, the findings of a lower risk of ovarian cancer associated with metformin and sulfonylureas in the present study (Tables and ) and the inhibitory effects of sulfonylureas on ovarian cancer cell growth in previous in vitro studies provide a good rationale for future exploration on the combined use of metformin and sulfonylureas for the prevention and treatment of ovarian cancer.…”

Section: Discussionsupporting

confidence: 94%

Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus

Tseng

2015

Diabetes Metabolism Res

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BACKGROUND:Whether metformin therapy affects ovarian cancer risk in Asian patients with type 2 diabetes mellitus (T2DM) has not been investigated. A time-dependent approach was used to calculate ovarian cancer incidence and estimate hazard ratios by Cox regression for never-users (as referent group), ever-users, and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). METHODS: RESULTS: CONCLUSIONS:Metformin use is associated with a decreased risk of ovarian cancer.

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Section: Discussionsupporting

confidence: 94%

Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus

Tseng

2015

Diabetes Metabolism Res

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“…First-generation DSUs, which are structurally similar to glibenclamide with an unknown anticancer mechanism, reached clinical application in some cases but with poor tolerability and disappointing results [50,54,55].…”

Section: Discussionmentioning

confidence: 99%

Section: From Glibenclamide To Dsusmentioning

confidence: 99%

“…The anticancer effects of sulofenur on solid tumors were also explored in phase I and II clinical trials [50,54,55]. On the basis of partial response observed in the phase I trial in a ovarian cancer patient [50], the phase II trial was designed to elucidate response rates and toxicity profile in stage III-IV previously treated ovarian cancer patients [54]. Sulofenur at the daily dose of 800 mg/m 2 showed prolonged stable disease (median: 20 weeks) in 42% of the study population and partial response (6.5-18 weeks) in 15% of the patients.…”

Section: From Glibenclamide To Dsusmentioning

confidence: 99%

“…The main limitation of glibenclamide and other sulfonylureas is the lack of clinical studies, probably because the principal mechanism of action has not been identified yet. First-generation DSUs, which are structurally similar to glibenclamide with an unknown anticancer mechanism, reached clinical application in some cases but with poor tolerability and disappointing results [50,54,55].…”

Section: Cmementioning

confidence: 99%

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Effects of Sulfonylureas on Tumor Growth: A Review of the Literature

et al. 2013

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Type 2 diabetes mellitus patients are at higher cancer risk, probably because of hyperinsulinemia and insulin growth factor 1 pathway activation. The effects of antidiabetic drugs on cancer risk have been described and discussed in several studies suggesting opposite effects of the biguanide metformin and sulfonylureas on cancer incidence and mortality. The anticancer mechanisms of metformin have been clarified, and some clinical studies, particularly in breast cancer patients, have been published or are currently ongoing; however, data about the effects ofsulfonylureasoncancergrowtharelessconsistent.Theaimsof thisworkaretoreviewpreclinicalevidenceofsecond-generation sulfonylureas effects on tumor growth, to clarify the potential mechanisms of action, and to identify possible metabolic targets for patient selection. Most evidence is on the adenosine triphosphate-sensitive potassium channels inhibitor glibenclamide, which interacts with reactive oxygen species production thus inducingcancercelldeath.Amongdiarylsulfonylureas,next-generation DW2282 derivatives are particularly promising because of the proapoptotic activity in multidrug-resistant cells. TheOncologist 2013;18:1118 -1125 Implications for Practice: The effects of anti-diabetic drugs on cancer risk have been described in several studies suggesting opposite effects of metformin and sulfonylureas on cancer incidence and mortality, respectively. Although the anticancer mechanisms of metformin have been clarified, no univocal data about sulfonylureas' effects on cancer growth are available. No previous review articles about the same topic have been published; therefore, there is conflicting evidence about the real role of different compounds of the sulfonylurea family on cancer cell growth. This article highlights specific proapoptotic pathways involved in the anticancer effects of these drugs, which might help in the identification of metabolic targets for preclinical and clinical study design and patient selection.

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Effect of DW2282 on the induction of methemoglobinemia, hypoglycemia or WBC count and hematological changes

et al. 1999

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DW2282,(S)-(+)-4-phenyl-1-[1-(4-aminobenzoyl)-indoline-5-sulfonyl] -4,5-dihydro-2-imidazolone hydrochloride, is a new anticancer agent which is thought to exhibit a characteristic mechanism of action in the inhibition of tumor growth. In this study, we estimated the toxicities of DW2282 in mice. When mice were orally dosed for five consecutive days at the dosages of 50, 100 and 150 mg/kg, DW2282 did not induce methemoglobinemia and hypoglycemia at any of these doses. However, increased ALT and AST values were observed in the 150 mg/kg dosing group, and white blood cells (WBC) were significantly decreased at all doses. However, the changes in WBC count, ALT and AST immediately reversed after the cessation of drug administration. In addition, we found that DW2282 did not cause an increase in hemolysis in human blood. Taken together, these data suggested that DW2282 may have a relatively low level of toxicity, and that there may be a quick recovery from any toxicity it does produce.

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Antitumor Activity and Clinical Pharmacology of Sulofenur in Ovarian Cancer

Abstract: The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified.

Cited by 12 publications

References 0 publications

Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus

Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus

Effects of Sulfonylureas on Tumor Growth: A Review of the Literature

Effect of DW2282 on the induction of methemoglobinemia, hypoglycemia or WBC count and hematological changes

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