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  Exisulind

Exisulind is an oral selective apoptotic antineoplastic drug which inhibits the cyclic GMP phosphodiesterase.

History of discovering exisulind: Exisulind, the sulfone derivative of sulindac, is the lead compound in a series of selective apoptotic antineoplastic drugs (SAANDs) being developed by OSI Pharmaceuticals. The compounds were originally developed by Cell Pathways, which was acquired by, and integrated into, OSI Pharmaceuticals in June 2003. Exisulind inhibits the enzyme cyclic GMP phosphodiesterase (GMP-PDE), overexpressed in precancerous and cancerous colorectal cells, and induces apoptosis in such cells with minimal effects on normal cells. This apoptotic effect is independent of COX I or COX II inhibition, p53, Bcl-2, or cell-cycle arrest. Preclinical evidence suggests that exisulind also inhibits angiogenesis. Cell Pathways has formed sales and distribution agreements with three healthcare-related companies in the US for its future marketing and support campaign for exisulind. Innovex will hire and train sales representatives for Cell Pathways to launch and promote exisulind, Livingston Healthcare Services will be responsible for customer service, order and distribution administration, and Lash Group will be responsible for the development and implementation of reimbursement support services for exisulind. Cell Pathways has issued an exclusive licence for exisulind to Paladin Labs of Montreal, Canada. The agreement allows Paladin exclusive rights to commercialise the drug in Canada. In August 1999 Cell Pathways submitted an NDA application to the US FDA for exisulind (Aptosyn) for the treatment of familial adenomatous polyposis (FAP). However, in September 2000, the FDA announced that it had found deficiencies in the safety and efficacy data of Cell Pathways' NDA, and returned a non-approvable letter to the company. Cell Pathways then initiated another phase III study of the agent in combination with Aventis' docetaxel and comparing combination therapy with docetaxel alone. Exisulind has fast-track designation for FAP in the US. Phase I and II paediatric trials are also underway in the US. Cell Pathways announced in April 2000 that it had completed enrollment in an open-label phase II study in children with familial adenomatous polyposis (FAP). Patients will be evaluated to determine whether polyp numbers have been reduced after 1 year relative to baseline. In June 2000, Cell Pathways announced the results of a 1-year extension of a 1997-1999 phase III trial that showed that exisulind significantly reduced polyp formation in patients with FAP. Enrollment of 282 patients in a multicentre, placebo-controlled phase III trial for the treatment of sporadic colonic polyps was completed in the US in May 1999. In its 2003 Annual Report, Paladin Labs announced that it is conducting a phase III study of exisulind in patients with prostate cancer in Canada. Exisulind has completed a pivotal phase II/III trial for preventing the recurrence of prostate cancer in the US. Two phase II prostate cancer trials were initiated in June 1999. The first study assessed the efficacy of exisulind in 15 patients who had undergone prostatectomy, were receiving LHRH-agonist hormone therapy and had increasing PSA levels (study EX1001). The second trial was to enroll 20 hormone-refractory patients scheduled for radical prostatectomy within 2-8 weeks of diagnosis (study EX1004). This study compared the effect of exisulind + docetaxel on the rate of apoptosis and GMP-PDE expression in premalignant or malignant and normal prostate tissue. Cell Pathways and Rhône-Poulenc Rorer (now Aventis) agreed to collaborate on clinical trials of exisulind in combination with docetaxel in the treatment of various solid tumours. The first phase I/II trial (study 026) was to enroll previously untreated patients with non-small cell lung cancer (NSCLC). OSI Pharmaceuticals and Bristol-Myers Squibb are conducting a phase I/II trial (study EX 2002) of exisulind in combination with paclitaxel and carboplatin as first-line treatment for patients with NSCLC. Both companies will share costs and information gathered from the SCLC. Both companies will share costs and information gathered from the trial. A phase I/II trial (study EX 2006) of weekly paclitaxel and carboplatin combined with exisulind is also underway in patients with advanced NSCLC. Cell Pathways and Glaxo Wellcome are cooperating in supporting a clinical trial (study EX 2004) of exisulind in combination with vinorelbine as first-line treatment for elderly patients with advanced NSCLC. The study will be conducted at the University of Wisconsin, and the two companies will share the costs of the trial while maintaining the rights to their respective compounds. Cell Pathways and Eli Lilly have a phase I/II trial (study EX 2005) of exisulind in combination with gemcitabine underway in patients with NSCLC. This study will investigate the efficacy and tolerability of escalating doses of exisulind in combination with a standard gemcitabine regimen. The Cancer and Leukaemia Group B (CALGB) initiated a phase II study of exisulind in combination with etoposide and carboplatin in patients with small cell lung cancer in the US in September 2002. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II study in NSCLC patients in September 2002 that will investigate the effects of exisulind in combination with gemcitabine and carboplatin. The objectives of the two studies are to determine the 12-month survival rate and response rates following treatment with the combination regimens. Patents covering the mechanism of action of exisulind have been allowed in Europe and Japan, and extend to the methods of identifying compounds that selectively stimulate apoptosis in precancerous and cancerous cells. (source: Drugs R D. 2004;5(4):220-6. http://www.ncbi.nlm.nih.gov/pubmed/15230629).

Current developer:    Cell Pathways Inc., OSI Pharmaceuticals.

Highlight on recent research using exisulind

Data published in 2010.

Curcumin potentiates the pro-apoptotic effects of sulindac sulfone in colorectal cancer.  OBJECTIVE:  The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment.  CONCLUSIONS:  Curcumin augments the therapeutic effects of SFN. This may be clinically important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC. (source: Expert Opin Investig Drugs. 2010 Apr;19 Suppl 1:S117-24. Giladi N, Kazanov D, Shpitz B, Aroch I, Kraus S, Arber N. Sapir Medical Center, Department of Surgery B, Kfar Saba, Tel Aviv, Israel.)

Data published in 2010:

Sulindac sulfone induces a decrease of beta-catenin in HNSCC. BACKGROUND: The most common neoplasm arising in the upper gastrointestinal tract is head and neck squamous cell carcinoma (HNSCC). This is an aggressive epithelial malignancy. Many growth factors and cytokines have been discovered that are responsible for the growth and formation of tumours. Among these factors, beta-catenin is considered to be the most important for reducing cell-cell adhesions in malignant tissue. The degradation of beta-catenin triggers apoptosis by different routes. Sulindac sulfone has been shown to induce apoptosis in several different tumours. In the present study, we surveyed the concentration of beta-catenin in an HNSCC line after incubation with different concentrations of sulindac sulfone. CONCLUSION:  In this study, sulindac sulfone reduced levels of secreted beta-catenin in the HNSCC cell line UM-SCC 11A after 48 hours of incubation. It is presumed that reduction of cell-cell adhesion, which is predominately affected by beta-catenin, is an essential step in the progression from localized malignancy to stromal and vascular invasion and ultimately metastatic disease. The reduction in the level of mural expression of beta-catenin has been associated with loss of differentiation in laryngeal carcinomas. Thus, prevention of intracellular beta-catenin accumulation is regarded as an attractive target for chemopreventive agents. (source: Anticancer Res. 2010 Feb;30(2):339-43. Sauter A, Soulsby H, Hormann K, Naim R. Department of Otolaryngology, Head and Neck Surgery, Universitaets-HNO-Klinik, Theodor-Kutzer-Ufer, D-68135 Mannheim, Germany. alexander.sauter@gmail.com)

Data published in 2009:

A phase II study of carboplatin, etoposide, and exisulind in patients with extensive small cell lung cancer: CALGB 30104.  PURPOSE:  To assess the efficacy and toxicity of carboplatin, etoposide, and exisulind as initial therapy for extensive stage small cell lung cancer.  CONCLUSIONS: The addition of exisulind to a standard regimen of carboplatin and etoposide did not improve outcomes compared with historic controls treated with chemotherapy alone. Further evaluation of this regimen in small cell lung cancer is not warranted. (source: J Thorac Oncol. 2009 Feb;4(2):220-6.)

Data punlished in 2008:

A phase II study of estramustine, docetaxel, and exisulind in patients with hormone- refractory prostate cancer: results of cancer and leukemia group B trial 90004. PURPOSE: Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug. CONCLUSION: The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine. (source: Clin Genitourin Cancer. 2008 Sep;6(2):110-6., http://www.ncbi.nlm.nih.gov/pubmed/18824434)

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2: Stępnik M, Ferlińska M, Smok-Pieniążek A, Gradecka-Meesters D, Arkusz J, Stańczyk M. Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines. Med Oncol. 2011 Apr 27. [Epub ahead of print] PubMed PMID: 21523454.

3: Stępnik M, Ferlińska M, Smok-Pieniążek A, Gradecka-Meesters D, Arkusz J, Stańczyk M. Sulindac and its metabolites: Sulindac sulfide and sulindac sulfone enhance cytotoxic effects of arsenic trioxide on leukemic cell lines. Toxicol In Vitro. 2011 Aug;25(5):1075-84. Epub 2011 Apr 15. PubMed PMID: 21515355.

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5: Krier F, Brion M, Debrus B, Lebrun P, Driesen A, Ziemons E, Evrard B, Hubert P. Optimisation and validation of a fast HPLC method for the quantification of sulindac and its related impurities. J Pharm Biomed Anal. 2011 Mar 25;54(4):694-700. Epub 2010 Nov 3. PubMed PMID: 21131156.

6: Lee JK, Paine MF, Brouwer KL. Sulindac and its metabolites inhibit multiple transport proteins in rat and human hepatocytes. J Pharmacol Exp Ther. 2010 Aug;334(2):410-8. Epub 2010 Apr 29. PubMed PMID: 20430841; PubMed Central PMCID: PMC2913772.

7: Giladi N, Kazanov D, Shpitz B, Aroch I, Kraus S, Arber N. Curcumin potentiates the pro-apoptotic effects of sulindac sulfone in colorectal cancer. Expert Opin Investig Drugs. 2010 Apr;19 Suppl 1:S117-24. PubMed PMID: 20374023.

8: Sauter A, Soulsby H, Hormann K, Naim R. Sulindac sulfone induces a decrease of beta-catenin in HNSCC. Anticancer Res. 2010 Feb;30(2):339-43. PubMed PMID: 20332437.

9: Pangburn HA, Ahnen DJ, Rice PL. Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor. Cancer Prev Res (Phila). 2010 Apr;3(4):560-72. Epub 2010 Mar 23. PubMed PMID: 20332299.

10: Steinbrink SD, Pergola C, Bühring U, George S, Metzner J, Fischer AS, Häfner AK, Wisniewska JM, Geisslinger G, Werz O, Steinhilber D, Maier TJ. Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations. Cell Mol Life Sci. 2010 Mar;67(5):797-806. Epub 2009 Nov 29. PubMed PMID: 20091083.

11: Govindan R, Wang X, Baggstrom MQ, Burdette-Radoux S, Hodgson L, Vokes EE, Green MR; Cancer and Leukemia Group B. A phase II study of carboplatin, etoposide, and exisulind in patients with extensive small cell lung cancer: CALGB 30104. J Thorac Oncol. 2009 Feb;4(2):220-6. PubMed PMID: 19179900.

12: Dawson NA, Halabi S, Ou SS, Biggs DD, Kessinger A, Vogelzang N, Clamon GH, Nanus DM, Kelly WK, Small EJ; Cancer And Leukemia Group B. A phase II study of estramustine, docetaxel, and exisulind in patients with hormone- refractory prostate cancer: results of cancer and leukemia group B trial 90004. Clin Genitourin Cancer. 2008 Sep;6(2):110-6. PubMed PMID: 18824434.

13: Attia S, Traynor AM, Kim K, Merchant JJ, Hoang T, Ahuja HG, Beatty PA, Hansen RM, Masters GA, Oettel KR, Shapiro GR, Larson MM, Larson ML, Schiller JH. Phase I/II study of vinorelbine and exisulind as first-line treatment of advanced non-small cell lung cancer in patients at least 70 years old: a wisconsin oncology network study. J Thorac Oncol. 2008 Sep;3(9):1018-25. PubMed PMID: 18758305; PubMed Central PMCID: PMC2562273.

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19: Loveridge CJ, MacDonald AD, Thoms HC, Dunlop MG, Stark LA. The proapoptotic effects of sulindac, sulindac sulfone and indomethacin are mediated by nucleolar translocation of the RelA(p65) subunit of NF-kappaB. Oncogene. 2008 Apr 17;27(18):2648-55. Epub 2007 Dec 3. PubMed PMID: 18059344.

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21: Weiss GJ, Vokes EE, Bunn PA Jr, Magree L, Rusk J, Albert D, Kelly K. Docetaxel and exisulind in previously treated non-small cell lung cancer (NSCLC) patients: a multicenter, phase II clinical trial. J Thorac Oncol. 2007 Oct;2(10):933-8. PubMed PMID: 17909356.

22: Narayanan BA, Reddy BS, Bosland MC, Nargi D, Horton L, Randolph C, Narayanan NK. Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence. Clin Cancer Res. 2007 Oct 1;13(19):5965-73. PubMed PMID: 17908994.

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27: Masters GA, Li S, Dowlati A, Madajewicz S, Langer C, Schiller J, Johnson D. A phase II trial of carboplatin and gemcitabine with exisulind (IND #65,056) in patients with advanced non-small cell lung cancer: an Eastern Cooperative Oncology Group study (E1501). J Thorac Oncol. 2006 Sep;1(7):673-8. PubMed PMID: 17409935.

28: Hoang T, Kim K, Merchant J, Traynor AM, McGovern J, Oettel KR, Sanchez FA, Ahuja HG, Hensing TA, Larson M, Schiller JH. Phase I/II study of gemcitabine and exisulind as second-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2006 Mar;1(3):218-25. PubMed PMID: 17409860.

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32: Lim SJ, Lee YJ, Park DH, Lee E, Choi MK, Park W, Chun KH, Choi HG, Cho JS. Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis. Apoptosis. 2007 Feb;12(2):423-31. PubMed PMID: 17191116.

33: Bock JM, Menon SG, Goswami PC, Sinclair LL, Bedford NS, Jackson RE, Trask DK. Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition. Cancer Biol Ther. 2007 Jan;6(1):30-9. PubMed PMID: 17172818.

34: Leite S, Martins NM, Dorta DJ, Curti C, Uyemura SA, dos Santos AC. Mitochondrial uncoupling by the sulindac metabolite, sulindac sulfide. Basic Clin Pharmacol Toxicol. 2006 Oct;99(4):294-9. PubMed PMID: 17040214.

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36: Lim SJ, Lee YJ, Lee E. p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis. Oncol Rep. 2006 Nov;16(5):1131-5. PubMed PMID: 17016604.

37: Quidville V, Segond N, Lausson S, Frenkian M, Cohen R, Jullienne A. 15-Hydroxyprostaglandin-dehydrogenase is involved in anti-proliferative effect of non-steroidal anti-inflammatory drugs COX-1 inhibitors on a human medullary thyroid carcinoma cell line. Prostaglandins Other Lipid Mediat. 2006 Oct;81(1-2):14-30. Epub 2006 Sep 1. PubMed PMID: 16997128.

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39: Czibere A, Prall WC, Zerbini LF, Jäger M, Kobbe G, Knipp S, Libermann TA, Haas R, Aivado M. Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS. Br J Haematol. 2006 Nov;135(3):355-7. Epub 2006 Sep 15. PubMed PMID: 16978222.

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43: Naim R, Chang RC, Schultz J, Hormann K. Chemopreventive alteration of the cell-cell adhesion in head and neck squamous cell cancer. Oncol Rep. 2006 Aug;16(2):273-7. PubMed PMID: 16820902.

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45: Lim JT, Joe AK, Suzui M, Shimizu M, Masuda M, Weinstein IB. Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3478-84. PubMed PMID: 16740773.

46: Pitari GM, Li T, Baksh RI, Waldman SA. Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells. Mol Cancer Ther. 2006 May;5(5):1190-6. PubMed PMID: 16731751.

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