Tag: M.W=350-400

Pusztai, Lajos published the artcilePhase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer, Name: Sulindac sulfone, the publication is Journal of Clinical Oncology (2003), 21(18), 3454-3461, database is CAplus and MEDLINE.

We studied the safety and clin. activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC). All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m² for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing. The most common nonhematol. grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 wk; three patients experienced stable disease longer than 26 wk. Overall clin. benefit (complete response, partial response, or stable disease > 26 wk) was 23%. Fourteen specimens were available for immunohistochem. assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity. Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.

Journal of Clinical Oncology published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Name: Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Anonymous published the artcileExisulind. aptosyn, FGN 1, prevatac, sulindac sulfone, Formula: C20H17FO4S, the publication is Drugs in R&D (2004), 5(4), 220-226, database is CAplus.

A review. Exisulind [Aptosyn, FGN 1, Prevatac, sulindac sulfone], 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 cGMP 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. Preclin. 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 license 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 Sept. 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 pediatric trials are also underway in the US. Cell Pathways announced in Apr. 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 yr relative to baseline. In June 2000, Cell Pathways announced the results of a 1-yr 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 enrol 20 hormone-refractory patients scheduled for radical prostatectomy within 2-8 wk 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 Rhone-Poulenc Rorer (now Aventis) agreed to collaborate on clin. trials of.exisulind in combination with docetaxel in the treatment of various solid tumors. The first phase I/II trial (study 026) was to enrol 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 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 clin. 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 resp. 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 Leukemia Group B (CALGB) initiated a phase 11 study of exisulind in combination with etoposide and carboplatin in patients with small cell lung cancer in the US in Sept. 2002. The Eastern Cooperative Oncol. Group (ECOG) initiated a phase 11 study in NSCLC patients in Sept. 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-mo 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 cell.

Drugs in R&D published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Formula: C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Ashour, Abdelkader E. published the artcilePhosphodiesterase-5 inhibitors in the management of cancer, Synthetic Route of 59973-80-7, the publication is Asian Journal of Biomedical and Pharmaceutical Sciences (2013), 3(20), 1-5, 5 pp., database is CAplus.

A review. Selective phosphodiesterase type-5 (PDE5) inhibitors such as sildenafil, vardenafil and tadalafil are commonly used first-line therapy for erectile dysfunction (ED). The safety and high tolerability of these drugs has garnered substantial interest among researchers to investigate further beneficial nonerectogenic uses for such drugs. PDE5 expression has shown to be increased in several human malignancies, suggesting that this enzyme may play a role in tumorigenesis. This is supported by the reported anticancer activity of PDE5 inhibitors such as exisulinde and its analogs, as well as vardenafil. Further, PDE5 inhibitors have recently been reported to sensitize certain types of cancer to standard chemotherapeutic drugs. The aim of this review is to shed some light on the existing preclin. evidence supporting the use of PDE5 inhibitors as potential effective adjuncts in cancer chemotherapy and even as anticancer agents. I also showed our recent unpublished data with regard to the promising antitumor activity of vardenafil, a potent PDE5 inhibitor, against brain cancer.

Asian Journal of Biomedical and Pharmaceutical Sciences published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Synthetic Route of 59973-80-7.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Liu, Xiangguo published the artcileDeath Receptor Regulation and Celecoxib-Induced Apoptosis in Human Lung Cancer Cells, Name: Sulindac sulfone, the publication is Journal of the National Cancer Institute (2004), 96(23), 1769-1780, database is CAplus and MEDLINE.

Background: Celecoxib, a cyclooxygenase 2 inhibitor, has chemopreventive and therapeutic activities toward lung cancer and other epithelial malignancies. Celecoxib can induce apoptosis in various cancer cell lines through a mechanism that is independent of its cyclooxygenase 2 inhibitory activity but is otherwise largely uncharacterized. We investigated the mechanism of celecoxib-induced apoptosis further. Methods: All experiments were conducted in human non-small-cell lung carcinoma (NSCLC) cell lines; results in celecoxib-treated and untreated cells were compared. Cell survival was assessed with a sulforhodamine B assay. Apoptosis was assessed by DNA fragmentation with an ELISA, by terminal deoxynucleotidyltransferase-mediated dUTP nick-end-labeling (TUNEL) assay, and by western blot anal. of caspase activation. Death receptor gene and protein expression was detected by northern and western blot anal., resp. Gene silencing was achieved with small interfering RNA (siRNA) technol. Results: Celecoxib treatment decreased cell survival, activated caspase cascades, and increased DNA fragmentation, all of which were abrogated when caspase 8 expression was silenced with caspase 8 siRNA. Celecoxib treatment induced the expression of death receptors, particularly that of DR5. Overexpression of a dominant neg. Fas-associated death domain mutant, but not of BCL2, reduced the level of celecoxib-induced apoptosis, and silencing of DR5 expression by DR5 siRNA suppressed celecoxib-induced caspase 8 activation and apoptosis. Combination treatment with celecoxib and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced addnl. apoptosis. For example, survival of A549 cells was decreased with 50 μM celecoxib alone by 38.7% (95% confidence interval [CI] = 35.2% to 42.2%), with TRAIL alone by 29.3% (95% CI = 25.1% to 33.6%), but with their combination by 77.5% (95% CI = 74.5% to 79.5%), a greater than additive effect. Conclusion: Celecoxib appears to induce apoptosis in human NSCLC through the extrinsic death receptor pathway.

Journal of the National Cancer Institute published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Name: Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Zheng, Xuehua published the artcileThe molecular basis for inhibition of sulindac and its metabolites towards human aldose reductase, Safety of Sulindac sulfone, the publication is FEBS Letters (2012), 586(1), 55-59, database is CAplus and MEDLINE.

Sulindac (SLD) exhibits both the highest inhibitory activity towards human aldose reductase (AR) among popular non-steroidal anti-inflammatory drugs and clear beneficial clin. effects on Type 2 diabetes. However, the mol. basis for these properties is unclear. Here, we report that SLD and its pharmacol. active/inactive metabolites, SLD sulfide and SLD sulfone, are equally effective as un-competitive inhibitors of AR in vitro. Crystallog. anal. reveals that π-π stacking favored by the distinct scaffold of SLDs is pivotal to their high AR inhibitory activities. These results also suggest that SLD sulfone could be a potent lead compound for AR inhibition in vivo.

FEBS Letters published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C13H24INO4, Safety of Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Wu, Zhufeng published the artcileEstablishment of pharmacophore and VolSurf models to predict the substrates of UDP-glucuronosyltransferase1A3, Formula: C20H17FO4S, the publication is Xenobiotica (2015), 45(8), 653-662, database is CAplus and MEDLINE.

1. UDP-glucuronosyltransferase1A3 (UGT1A3) catalyzes glucuronidation of numerous xenobiotics/drugs. Here, we aimed to establish substrate selectivity models for UGT1A3 using the pharmacophore and VolSurf approaches. 2. Fifty structurally diverse substrates of UGT1A3 were collated from the literature. These substrates were divided into training (n = 34) and test sets (n = 16). The pharmacophore model was developed using the Discovery Studio 2.5 software. A user-defined feature (i.e. the glucuronidation site) was included in the program for model generation. The VolSurf model was derived using the VolSurf program implemented in SYBYL 8.0 software. 3. The pharmacophore model consisted of three features (i.e. one glucuronidation site and two hydrogen-bond acceptors). The activities of 81% of test set substrates were adequately predicted (deviated by less than one-log unit) by the model, suggestive of a satisfactory predictive power. The refined VolSurf model based on 22 mol. descriptors was statistically significant (r² = 0.793, q² = 0.606). It also processed a good predictability as the activities of 14 test set compounds were well predicted. The VolSurf model highlighted the chem. features (including large mol. size, hydrophilic regions and hydrogen-bonding groups) contributing to favored glucuronidation by UGT1A3. 4. In conclusion, two predictive 3D-QSAR models (i.e. the pharmacophore and VolSurf models) for UGT1A3 were successfully established. These models contributed to an improved understanding of the substrate preference of UGT1A3 and a more comprehensive prediction of UGT-mediated metabolism

Xenobiotica published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C38H24F4O4P2, Formula: C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Deguchi, Atsuko published the artcileActivation of Protein Kinase G Up-regulates Expression of 15-Lipoxygenase-1 in Human Colon Cancer Cells, Category: naphthyridine, the publication is Cancer Research (2005), 65(18), 8442-8447, database is CAplus and MEDLINE.

Recent studies indicate that the induction of apoptosis in human colon cancer cells by certain nonsteroidal anti-inflammatory drugs involves increased expression of 15-LOX-1 and synthesis of its major product 13-S-hydroxyoctadecadienoic acid (13-S-HODE). Evidence was obtained that this occurs via a cyclooxygenase-2 (COX-2)-independent mechanism, but the actual mechanism of induction of 15-LOX-1 by these compounds is not known. There is extensive evidence that treatment of SW480 human colon cancer cells with sulindac sulfone (Exisulind, Aptosyn) or the related derivative OSI-461, both of which inhibit cGMP-phosphodiesterases but lack COX-2 inhibitory activity, causes an increase in intracellular levels of cGMP, thus activating protein kinase G (PKG), which then activates pathways that lead to apoptosis. Therefore, in the present study, the authors examined the effects of various agents that cause increased cellular levels of cGMP on the expression of 15-LOX-1 in SW480 human colon cancer cells. Treatment of the cells with Exisulind, sulindac sulfide, OSI-461, the guanylyl cyclase activator YC-1, or the cell-permeable cGMP compound 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) caused an increase in cellular levels of 15-LOX-1. Exisulind, OSI-461, and 8-pCPT-cGMP also increased mRNA levels of 15-LOX-1, suggesting that the effects were at the level of transcription. The cGMP-phosphodiesterase inhibitors and YC-1 increased the production of 13-S-HODE, which is the linoleic acid metabolite of 15-LOX-1. Treatment of SW480 cells with the PKG inhibitor R_p-8-pCPT-cGMP blocked Exisulind-induced 15-LOX-1 expression. Furthermore, derivatives of SW480 cells that were engineered to stably overexpress wild-type PKG Iβ displayed increased cellular levels of 15-LOX-1 when compared with vector control cells. Taken together, these results provide evidence that the cGMP/PKG pathway can play an important role in the induction of 15-LOX-1 expression by nonsteroidal anti-inflammatory drugs and related agents.

Cancer Research published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Category: naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Kim, Ju-Young published the artcileActivation of Protein Kinase G (PKG) Reduces Neointimal Hyperplasia, Inhibits Platelet Aggregation, and Facilitates Re-endothelialization, Related Products of naphthyridine, the publication is Scientific Reports (2016), 36979, database is CAplus and MEDLINE.

In spite of its great success in reducing restenosis, drug-eluting stent (DES) has unfavorable aspects such as stent thrombosis and delayed re-endothelialization. We examined the effects of PKG activation by Exisulind on neointimal formation, platelet aggregation, and re-endothelialization. Exisulind significantly reduced VSMCs viability, cell cycle progression, migration, and neointimal hyperplasia after vascular injury in rat carotid arteries. Interestingly, in contrast to the effect on VSMC viability, Exisulind did not reduce the viability of endothelial cells. Increased PKG activity by Exisulind inhibited PDGF-stimulated phenotype change of VSMCs from a contractile to a synthetic form. Conversely, the use of PKG inhibitor or gene transfer of dominant-neg. PKG reversed the effects of Exisulind, resulting in the increased viability of VSMCs and neointimal formation. In addition, Exisulind facilitated the differentiation of peripheral blood mononuclear cells to endothelial lineage via PKG pathway, while inhibiting to VSMCs lineage, which was correlated with the enhanced re-endothelialization in vivo. Finally, Exisulind reduced platelet aggregation, which was mediated via PKG activation. This study demonstrated that Exisulind inhibits neointimal formation and platelet aggregation while increasing re-endothelialization via PKG pathway. These findings suggest that Exisulind could be a promising candidate drug of DES for the prevention of restenosis without other complications.

Scientific Reports published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Related Products of naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Allani, S. K. published the artcileSulindac induces differentiation of glioblastoma stem cells making them more sensitive to oxidative stress, Category: naphthyridine, the publication is Neoplasma (2018), 65(3), 376-388, database is CAplus and MEDLINE.

Glioblastoma tumors (GBM) are very heterogeneous, being comprised of several cell subtypes, including glioblastoma stem cells (GSC). These tumors have a high rate of recurrence after initial treatment and one of the most prevalent theories to explain this is the cancer stem cell theory, which proposes that glioblastomas arise from mutations that transform normal neural stem cells (NSC) into GSC, which are highly resistant to oxidative stress and anti-cancer therapies. To study the effect of sulindac on both normal and cancer stem cells, we have isolated normal neural stem cells (NSC), from mice hippocampi and glioblastoma stem cells (GSC) from a glioma cell line, U87. As expected from previous studies sulindac can protect normal astrocytes against oxidative stress. Sulindac induces differentiation of both NSC and GSC cells and sulindac upregulates neurogenesis in NSC. The differentiated NSC are also protected from oxidative stress damage, whereas the differentiation of GSC by sulindac increases the sensitivity of these cells to agents that cause oxidative stress. The S epimer of sulindac is more effective than the R epimer in inducing neuronal differentiation in both NSC and GSC. These results indicate that the ability of sulindac to induce GSC differentiation may have therapeutic value in preventing tumor recurrence.

Neoplasma published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Category: naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Kung, Hsiu-Ni published the artcileSulindac compounds facilitate the cytotoxicity of β-lapachone by up-regulation of NAD(P)H quinone oxidoreductase in human lung cancer cells, Product Details of C20H17FO4S, the publication is PLoS One (2014), 9(2), e88122/1-e88122/15, 15 pp., database is CAplus and MEDLINE.

β-Lapachone, a major component in an ethanol extract of Tabebuia avellanedae bark, is a promising potential therapeutic drug for various tumors, including lung cancer, the leading cause of cancer-related deaths worldwide. In the first part of this study, we found that apoptotic cell death induced in lung cancer cells by high concentrations of β-lapachone was mediated by increased activation of the pro-apoptotic factor JNK and decreased activation of the cell survival/proliferation factors PI3K, AKT, and ERK. In addition, β-lapachone toxicity was pos. correlated with the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in the tumor cells. In the second part, we found that the FDA-approved non-steroidal anti-inflammatory drug sulindac and its metabolites, sulindac sulfide and sulindac sulfone, increased NQO1 expression and activity in the lung adenocarcinoma cell lines CL1-1 and CL1-5, which have lower NQO1 levels and lower sensitivity to β-lapachone treatment than the A549 cell lines, and that inhibition of NQO1 by either dicoumarol treatment or NQO1 siRNA knockdown inhibited this sulindac-induced increase in β-lapachone cytotoxicity. In conclusion, sulindac and its metabolites synergistically increase the anticancer effects of β-lapachone primarily by increasing NQO1 activity and expression, and these two drugs may provide a novel combination therapy for lung cancers.

PLoS One published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Product Details of C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem