sulindac and Neoplasm-Metastasis

Current treatments for androgen-independent prostate cancer have not shown a definitive increase in survival. Several novel drugs have made their way through preclinical testing into early clinical trials. Targets discussed in this review include apoptosis, antiangiogenesis, growth factor receptors or associated tyrosine kinases, and tumor-associated antigens targeted by vaccines. Research in this area includes testing combinations of previously studied chemotherapeutic agents as well as identifying and testing novel agents. It is these drugs, either alone or in combination, that are designed to target strategic pathways to improve survival and increase quality of life in prostate cancer patients. This review focuses on the novel agents being tested with chemotherapy in metastatic prostate cancer.

Topics: Androgens; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Cancer Vaccines; Humans; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Randomized Controlled Trials as Topic; Sulindac; Thalidomide

In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind.. Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously.. All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added.. : Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Sulindac; Survival Analysis; Taxoids

We studied the safety and clinical 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 nonhematologic 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 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical 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.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 5; Deoxycytidine; Female; Fluorouracil; Humans; Immunohistochemistry; Middle Aged; Neoplasm Metastasis; Phosphoric Diester Hydrolases; Prodrugs; Sulindac

Store-operated Ca

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Caco-2 Cells; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Cell Movement; Colorectal Neoplasms; Humans; Intracellular Calcium-Sensing Proteins; Membrane Proteins; Neoplasm Metastasis; Prodrugs; Sulindac

Topics: Animals; Celecoxib; Cell Movement; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; HEK293 Cells; Humans; Inflammation; Interleukin-2; Male; Membrane Proteins; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Prostatic Neoplasms; Serine Endopeptidases; Sulindac; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The cooperation of adaptive immunity with pharmacologic therapy influences cancer progression. Though non-steroidal anti-inflammatory drugs (NSAIDs) have a long history of cancer prevention, it is unclear whether adaptive immune system affects the action of those drugs. In present study, we revealed a novel immunological mechanism of sulindac. Our data showed that sulindac had substantial efficacy as a single agent against 4T1 murine breast cancer and prolonged the survival of tumor-bearing mice. However, in the athymic nude mice, sulindac treatment was ineffective. Further in vivo T cell subsets depletion experiments showed that CD8+ T lymphocytes deficiency reversed the anti-tumor effect of sulindac. In addition, sulindac significantly reduced M2 macrophages recruitment, cancer-related inflammation and tumor angiogenesis. Our results advance our understanding of the mechanisms of NSAIDs, and more importantly, this will provide insight into rational drug design or antitumor immunotherapy.

Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Breast Neoplasms; Cell Line, Tumor; Cytokines; Disease Models, Animal; Humans; Immunologic Factors; Immunomodulation; Inflammation Mediators; Lymphocyte Depletion; Macrophages; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Sulindac; T-Lymphocyte Subsets; Tumor Burden; Tumor Microenvironment

Colon cancer metastasis is often associated with activation of the Wnt/β-catenin signaling pathway and high expression of the metastasis mediator S100A4. We previously demonstrated the transcriptional regulation of S100A4 by β-catenin and the importance of the interconnection of these cellular programs for metastasis. Here we probe the hypothesis that the nonsteroidal anti-inflammatory drug sulindac sulfide can inhibit colon cancer metastasis by intervening in β-catenin signaling and thereby interdicting S100A4. We treated colon cancer cell lines heterozygous for gain-of-function and wild-type β-catenin with sulindac. We analyzed sulindac's effects on β-catenin expression and subcellular localization, β-catenin binding to the T-cell factor (TCF)/S100A4 promoter complex, S100A4 promoter activity, S100A4 expression, cell motility, and proliferation. Mice intrasplenically transplanted with S100A4-overexpressing colon cancer cells were treated with sulindac. Tumor growth and metastasis, and their β-catenin and S100A4 expressions, were determined. We report the expression knockdown of β-catenin by sulindac, leading to its reduced nuclear accumulation. The binding of β-catenin to TCF was clearly lowered, resulting in reduced S100A4 promoter activity and expression. This correlated well with the inhibition of cell migration and invasion, which could be rescued by ectopic S100A4 expression. In mice, sulindac treatment resulted in reduced tumor growth in the spleen (P = .014) and decreased liver metastasis in a human colon cancer xenograft model (P = .025). Splenic tumors and liver metastases of sulindac-treated mice showed lowered β-catenin and S100A4 levels. These results suggest that modulators of β-catenin signaling such as sulindac offer potential as antimetastatic agents by interdicting S100A4 expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; beta Catenin; Cell Movement; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Liver; Mice; Neoplasm Metastasis; S100 Calcium-Binding Protein A4; S100 Proteins; Signal Transduction; Spleen; Sulindac; TCF Transcription Factors; Transcriptional Activation; Wnt Proteins

Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers. However, the relationship between expression of COX-2 and clinico-pathological or genotypic features has not been elucidated. To address the issue, expression of COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected in some gastric cancer cell lines without MSI at various levels, but not in those with MSI. Our results suggest that overexpression of COX-2 may play an important role in tumor progression of gastric cancer and also support the notion that gastric cancers with and without MSI represent distinctive pathways of carcinogenesis. We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999.

Topics: Adaptor Proteins, Signal Transducing; Aspirin; Base Pair Mismatch; Carrier Proteins; Cyclooxygenase 2; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Lymphatic Metastasis; Male; Membrane Proteins; Microsatellite Repeats; MutL Protein Homolog 1; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Staging; Nuclear Proteins; Phenotype; Prostaglandin-Endoperoxide Synthases; Stomach Neoplasms; Sulindac; Tumor Cells, Cultured

Recent epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in individuals who take nonsteroidal antiinflammatory drugs on a regular basis compared with those not taking these agents. One property shared by all of these drugs is their ability to inhibit cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. Human colon cancer cells (Caco-2) were permanently transfected with a COX-2 expression vector or the identical vector lacking the COX-2 insert. The Caco-2 cells, which constitutively expressed COX-2, acquired increased invasiveness compared with the parental Caco-2 cells or the vector transfected control cells. Biochemical changes associated with this phenotypic change included activation of metalloproteinase-2 and increased RNA levels for the membrane-type metalloproteinase. Increased invasiveness and prostaglandin production were reversed by treatment with sulindac sulfide, a known COX inhibitor. These studies demonstrate that constitutive expression of COX-2 can lead to phenotypic changes that alter the metastatic potential of colorectal cancer cells.

Topics: 3T3 Cells; Animals; Anti-Inflammatory Agents, Non-Steroidal; Caco-2 Cells; Colonic Neoplasms; Cyclooxygenase 2; Enzyme Activation; Humans; Isoenzymes; Membrane Proteins; Metalloendopeptidases; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Sulindac; Tumor Cells, Cultured