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 Indisulam

Description of Indisulam: Indisulam (E7070) is a carbonic anhydrase inhbitor, is also a novel synthetic sulfon-amide that targets the G1 phase of the cell cycle.. The potential antitumor activity of Indisulam was discovered through optimization of the structure-activity relationships of a series of sulfonamide structures. Indisulam causes a blockade in the G1/S transition through inhibition of the activation of both cyclin-dependent kinase 2 and cyclin E. Preclinical studies with Indisulam showed activity in multiple tumor types, most prominently in colon and lung cancer.  (source: Anticancer Drugs. 2002 Nov;13(10):989-97.).

Current developer:   Eisai Inc.

Phase II study of Indisulam: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels. CONCLUSIONS: Despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer. (source: Clin Cancer Res. 2007 Mar 15;13(6):1816-22.)

Nano-encapsulated indisulam: This study aimed to begin development of a nanomedicine containing indisulam solubilized in sterically stabilized micelles (SSMs) composed of DSPE-PEG(2000) or sterically stabilized mixed micelles (SSMMs) composed of DSPE-PEG(2000) plus egg phosphatidylcholine. Micelles were prepared by co-precipitation and reconstitution of drug and lipids. Particle size distributions of micellar formulations were determined by quasi-elastic light scattering. Amounts of solubilized drug were determined by reverse-phase high-performance liquid chromatography (RP-HPLC). In vitro cytotoxicity of indisulam in nanocarrier was determined on the MCF-7 cell line by the National Cancer Institute-developed sulforhodamine B assay. Optimal solubilized indisulam concentrations in 5 mM total lipid were 10 microg/mL for SSMMs and 400 microg/mL for SSMs. HPLC results demonstrated that the encapsulation capacity of both micelles was over 95%. In vitro studies showed that indisulam in micellar system was more effective than free indisulam. The optimized formulation was successfully freeze-dried without any addition of lyoprotectants or cryoprotectants. We conclude that SSMs are a promising nanocarrier for indisulam, and indisulam-SSMs should be developed further as a novel targeted nanomedicine. (source: Nanomedicine. 2009 Jun;5(2):178-83.)

1: Ozawa Y, Kusano K, Owa T, Yokoi A, Asada M, Yoshimatsu K. Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment. Cancer Chemother Pharmacol. 2012 Feb 17. [Epub ahead of print] PubMed PMID: 22349812.

2: Zandvliet AS, Schellens JH, Copalu W, Beijnen JH, Huitema AD. Covariate-based dose individualization of the cytotoxic drug indisulam to reduce the risk of severe myelosuppression. J Pharmacokinet Pharmacodyn. 2009 Feb;36(1):39-62. Epub 2009 Feb 7. PubMed PMID: 19199010.

3: Cesur H, Rubinstein I, Pai A, Onyüksel H. Self-associated indisulam in phospholipid-based nanomicelles: a potential nanomedicine for cancer. Nanomedicine. 2009 Jun;5(2):178-83. Epub 2008 Dec 13. PubMed PMID: 19071064; PubMed Central PMCID: PMC2785016.

4: Zandvliet AS, Schellens JH, Dittrich C, Wanders J, Beijnen JH, Huitema AD. Population pharmacokinetic and pharmacodynamic analysis to support treatment optimization of combination chemotherapy with indisulam and carboplatin. Br J Clin Pharmacol. 2008 Oct;66(4):485-97. Epub 2008 May 29. PubMed PMID: 18637887; PubMed Central PMCID: PMC2561111.

5: Siegel-Lakhai WS, Zandvliet AS, Huitema AD, Tibben MM, Milano G, Girre V, Diéras V, King A, Richmond E, Wanders J, Beijnen JH, Schellens JH. A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours. Br J Cancer. 2008 Apr 22;98(8):1320-6. Epub 2008 Apr 15. PubMed PMID: 18414469; PubMed Central PMCID: PMC2361705.

6: Baur M, Gneist M, Owa T, Dittrich C. Clinical complete long-term remission of a patient with metastatic malignant melanoma under therapy with indisulam (E7070). Melanoma Res. 2007 Oct;17(5):329-31. PubMed PMID: 17885589.

7: Zandvliet AS, Siegel-Lakhai WS, Beijnen JH, Copalu W, Etienne-Grimaldi MC, Milano G, Schellens JH, Huitema AD. PK/PD model of indisulam and capecitabine: interaction causes excessive myelosuppression. Clin Pharmacol Ther. 2008 Jun;83(6):829-39. Epub 2007 Sep 12. PubMed PMID: 17851564.

8: Zandvliet AS, Huitema AD, Copalu W, Yamada Y, Tamura T, Beijnen JH, Schellens JH. CYP2C9 and CYP2C19 polymorphic forms are related to increased indisulam exposure and higher risk of severe hematologic toxicity. Clin Cancer Res. 2007 May 15;13(10):2970-6. PubMed PMID: 17504998.

9: Talbot DC, von Pawel J, Cattell E, Yule SM, Johnston C, Zandvliet AS, Huitema AD, Norbury CJ, Ellis P, Bosquee L, Reck M. A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2007 Mar 15;13(6):1816-22. PubMed PMID: 17363538.

10: Dittrich C, Zandvliet AS, Gneist M, Huitema AD, King AA, Wanders J. A phase I and pharmacokinetic study of indisulam in combination with carboplatin. Br J Cancer. 2007 Feb 26;96(4):559-66. Epub 2007 Feb 6. PubMed PMID: 17285128; PubMed Central PMCID: PMC2360043.

11: Zandvliet AS, Schellens JH, Copalu W, Beijnen JH, Huitema AD. A semi-physiological population pharmacokinetic model describing the non-linear disposition of indisulam. J Pharmacokinet Pharmacodyn. 2006 Oct;33(5):543-70. Epub 2006 Sep 1. PubMed PMID: 16946998.

12: Zandvliet AS, Copalu W, Schellens JH, Beijnen JH, Huitema AD. Saturable binding of indisulam to plasma proteins and distribution to human erythrocytes. Drug Metab Dispos. 2006 Jun;34(6):1041-6. Epub 2006 Mar 24. PubMed PMID: 16565173.

13: Beumer JH, Hillebrand MJ, Pluim D, Rosing H, Foley K, Yule SM, Schellens JH, Beijnen JH. Human metabolism of [(14)C]indisulam following i.v. infusion in cancer patients. Invest New Drugs. 2005 Aug;23(4):317-30. PubMed PMID: 16012791.

14: van Kesteren C, Zandvliet AS, Karlsson MO, Mathôt RA, Punt CJ, Armand JP, Raymond E, Huitema AD, Dittrich C, Dumez H, Roché HH, Droz JP, Ravic M, Yule SM, Wanders J, Beijnen JH, Fumoleau P, Schellens JH. Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam. Invest New Drugs. 2005 Jun;23(3):225-34. PubMed PMID: 15868378.

15: Beumer JH, Rosing H, Hillebrand MJ, Nan-Offeringa LG, Foley K, Yule SM, Heck AJ, Schellens JH, Beijnen JH. Quantitative determination of the novel anticancer drug E7070 (indisulam) and its metabolite (1,4-benzenedisulphonamide) in human plasma, urine and faeces by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 2004;18(23):2839-48. PubMed PMID: 15517526.

16: Supuran CT. Indisulam. Eisai. IDrugs. 2002 Nov;5(11):1075-9. PubMed PMID: 12800061.

17: Supuran CT. Indisulam: an anticancer sulfonamide in clinical development. Expert Opin Investig Drugs. 2003 Feb;12(2):283-7. Review. PubMed PMID: 12556221.