sulindac and Carcinoma--Non-Small-Cell-Lung

Lung cancer is the leading cause of cancer death in the United States. The majority of patients with non-small cell lung cancers present with inoperable disease because of the presence of metastases to regional lymph nodes or other metastatic sites. About one third of patients have stage IV disease with metastases to distant organs at the time of diagnosis. The prognosis for these patients is very poor. With best supportive care the median survival is only 4 months and the 1-year survival rate is 10% to 15%. Current chemotherapy combinations improve the survival and quality of life for patients with advanced non-small cell lung cancer. With two-drug combinations, median survival is increased to 8 months or more and 1-year survival is increased to 35% to 40%. Still, complete response rates are low and more than 80% of patients die within 1 year of diagnosis. The improvements created by current therapies led to studies of chemotherapy in the second-line setting. Docetaxel has been shown to improve survival of patients who failed platinum-based chemotherapy and was approved by the U.S. Food and Drug Administration for therapy in this setting. However, response rates were very low and survival very short. Therefore, new therapies are urgently needed. Exisulind is a novel oral anticancer agent that holds promise for the treatment of patients with advanced non-small cell lung cancer. Exisulind was originally developed as a chemoprevention agent for colorectal cancer. Preclinical studies showed that exisulind could prevent polyp formation and inhibit the growth of colorectal cancers. Subsequent preclinical studies showed that exisulind also inhibited the growth of human breast, prostate, and lung cancers. Phase I clinical studies showed that twice-daily oral doses could be given safely and would provide peak concentrations that were equivalent to those required for in vitro effects. These observations lead to the studies of the combination of exisulind and docetaxel in preclinical and clinical studies in human lung cancer described in this article.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Disease Models, Animal; Docetaxel; Humans; Immunohistochemistry; Lung Neoplasms; Mice; Paclitaxel; Rats; Sulindac; Survival Analysis; Taxoids; Treatment Outcome; Tumor Cells, Cultured

Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).. At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index.. Slower than anticipated recruitment led to trial closure after randomizing participants (n=31 and n=30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p=0.0005) and sulindac (30 versus 10; p=0.0003) arms, but the difference between arms was not statistically significant (p=0.92).. Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Chemoprevention; Female; Humans; Interdisciplinary Studies; Lung Neoplasms; Male; Middle Aged; Smoking; Sulindac; Treatment Outcome

Exisulind is an apoptotic agent with preclinical activity in non-small cell lung cancer (NSCLC). Vinorelbine is safe and effective in older patients with advanced NSCLC. We assessed these agents together as palliative treatment for older patients with advanced NSCLC.. Chemotherapy-naive patients >/=70-years-old with stage IIIB-IV NSCLC and a performance status (PS) /=3 neutropenia occurred in 14/30 patients. Two patients experienced neutropenic fever. There were no complete responses, one partial response and 12 patients with stable disease as their best response. The objective response rate was 4.0% (95% CI: 0.1-20.4%). Phase II median time-to-progression was 4.7 months (95% CI: 3.1-9.3 months) and median OS was 9.6 months (95% CI: 6.6-19.1 months).. This combination is safe, seems to have activity in the elderly with advanced NSCLC and a PS

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Neoplasm Staging; Prognosis; Sulindac; Survival Rate; Vinblastine; Vinorelbine

This multicenter, phase II clinical trial was conducted to evaluate the activity of the combination of docetaxel and exisulind in advanced non-small cell lung cancer (NSCLC) patients who failed a prior platinum-containing regimen.. Patients with measurable disease and adequate organ function received exisulind (250 mg) given orally, twice daily, and docetaxel (36 mg/m) administered intravenously on days 1, 8, and 15 of a 4-week cycle for up to six cycles. In the absence of disease progression or intolerable side effects, patients continued taking 250 mg of exisulind orally, twice daily.. Thirty-three patients (median age 60 years; range 34-77; median performance status 1) were enrolled. There were no objective responses documented. Sixteen patients [48%, 95% confidence interval (CI): 31%-66%] had stable disease after 8 weeks of treatment. Median progression-free survival (PFS) was 2.1 months (95% CI: 1.5-3.2 months); median overall survival time was 8.0 months (range 0.2-25.9 months). Toxicity was moderate, with dose adjustment for adverse event/toxicity required for docetaxel or exisulind in 13 (39.3%) patients. Grade 3/4 lymphopenia, neutropenia, and anemia occurred in 48.5%, 12.1%, and 9.1% of patients, respectively. Grade 3 or greater toxicity was seen in 12.1%, 6.1%, and 3% of patients for nausea/vomiting, dyspnea, and abdominal pain, respectively.. Treatment with exisulind and weekly docetaxel was not active in NSCLC patients who failed a prior platinum-containing regimen. Further study of this combination does not seem warranted.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Combined Modality Therapy; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Radiotherapy Dosage; Remission Induction; Sulindac; Survival Rate; Taxoids; Treatment Outcome

The study was designed to evaluate the safety and efficacy of exisulind, a selective apoptotic antineoplastic drug, in combination with gemcitabine as second-line therapy in patients with progressing advanced non-small cell lung cancer.. Patients whose disease progressed more than 3 months from completion of first-line chemotherapy were eligible for this phase I/II trial. Primary end points were maximally tolerated dose and time to progression. Patients in the phase I portion of the study were treated with gemcitabine (1250 mg/m) in combination with three escalated dose levels of exisulind. Treatment involved six cycles of gemcitabine and exisulind followed by exisulind maintenance. The study was subsequently expanded to phase II.. Thirty-nine patients (15 in phase I and 24 in phase II) were treated. The regimen was well tolerated with grade 3 fatigue and grade 3 constipation being dose-limiting toxicities. The maximally tolerated dose was not reached. Dose level 3 of exisulind (250 mg twice daily) in combination with gemcitabine was used for phase II. The overall response rates were 7% (phase I), 17% (phase II), and 13% (all). Median time to progression and median and 1-year survival, respectively, were 3.7 and 9.7 months and 33% (phase I); 4.3 and 9.4 months and 41% (phase II); and 4.1 and 9.4 months and 39% (all).. Although the study met its primary end point of improving time to progression (more than 4.1 months in phase II), we did not observe a clear survival advantage and thus do not plan to further investigate this schedule of gemcitabine and exisulind.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease Progression; Female; Follow-Up Studies; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Sulindac; Survival Analysis; Treatment Outcome; Vomiting

Carboplatin and gemcitabine are one standard regimen for patients with advanced non-small cell lung cancer (NSCLC). The oral proapoptotic agent exisulind is a cyclic guanosine monophosphate phosphodiesterase that increases apoptosis in vitro. We performed a phase II trial of carboplatin and gemcitabine with exisulind in patients with advanced NSCLC.. Gemcitabine (1000 mg/m days 1 and 8) and carboplatin (AUC = 5 day 1) were administered every 21 days, with exisulind orally at 250 mg orally twice daily continuously, starting day 1. The primary objective was to evaluate the 18-month survival. Secondary objectives included response rate, progression-free survival, and toxicities. Eligibility included stage IIIB (pleural effusion) or stage IV NSCLC, no previous chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.. Of 57 eligible patients treated, 34 patients were male and 23 female, 42 had stage IV, six stage IIIB, and nine had recurrent disease. The median age was 63 years (range, 37-83). Twenty-six patients had an ECOG PS of 0 and 31 had a PS of 1. The majority of grade 3-4 toxicities were hematologic. Grade 3-4 nonhematologic toxicity seen in >5% of patients included nausea/vomiting in 16% and fatigue in 23% of patients. The overall response rate was 19.3%. Median progression-free survival was 4.7 months. Median overall survival was 9.0 months. Eighteen-month overall survival was 30%.. The chemotherapy combination of gemcitabine and carboplatin with the oral proapoptotic agent exisulind is generally well tolerated with principally hematologic toxicity. The statistical endpoint of 17 patients alive at 18 months was met, but given ongoing developments in advanced NSCLC, ECOG will not be pursuing additional trials of exisulind in NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Female; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Sulindac; Survival Rate

Exisulind is a sulfone derivative of sulindac that induces apoptosis and demonstrates synergy with docetaxel in lung cancer models. This study evaluated the safety, efficacy, and pharmacokinetic interactions of exisulind and docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer (NSCLC). Fifty-seven patients received 218 cycles of docetaxel (75 mg/m2) and carboplatin (area under the curve, 5.0) in combination with exisulind (125-250 mg orally twice daily). Two complete responses and 9 partial responses were observed among the 47 patients assessable for response (overall response rate, 23%). The median duration of response was 5.9 months and median survival was 9.4 months. The 1- and 2-year survival rates are 35% and 14%, respectively. The hematologic toxicities were consistent with those previously reported with docetaxel/carboplatin. The most common nonhematologic toxicities were mild to moderate fatigue, anorexia, nausea, and vomiting. The addition of exisulind to the chemotherapy regimen did not interfere with the metabolism or elimination of docetaxel and vice versa, and docetaxel did not interfere with the pharmacokinetic parameters of exisulind. This trial did not allow direct comparison of patients receiving docetaxel/carboplatin with and without exisulind, but when compared with historical data of docetaxel/carboplatin alone, the addition of exisulind does not appear to enhance antitumor activity, duration of response, or survival. Although preclinical data demonstrate increased apoptosis and prolonged survival for the combination of exisulind and docetaxel, multiple clinical trials do not support further clinical development of this combination regimen in patients with advanced NSCLC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Carcinoma, Non-Small-Cell Lung; Docetaxel; Female; Humans; Lung Neoplasms; Male; Middle Aged; Sulindac; Taxoids

Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation.

Topics: Administration, Inhalation; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; Dose-Response Relationship, Drug; ErbB Receptors; Humans; Lung Neoplasms; Mitochondria; Mitogen-Activated Protein Kinases; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; raf Kinases; Signal Transduction; Sulindac; Tumor Burden; Xenograft Model Antitumor Assays

Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit growth of non-small-cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Because these agents engage off-target pathways, we have assessed the effects of PPARgamma by overexpressing the protein in NSCLC cells. We reported previously that increased PPARgamma inhibits transformed growth and invasiveness and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of cyclooxygenase-2 (COX-2) and produce high levels of prostaglandin E(2) (PGE(2)). The goal of these studies was to identify the molecular mechanisms whereby PPARgamma inhibits tumorigenesis. Increased PPARgamma inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE(2) production. Suppression of COX-2 was mediated through increased activity of the tumor suppressor phosphatase and tensin homolog, leading to decreased levels of phospho-Akt and inhibition of nuclear factor-kappaB activity. Pharmacological inhibition of PGE(2) production mimicked the effects of PPARgamma on epithelial differentiation in three-dimensional culture, and exogenous PGE(2) reversed the effects of increased PPARgamma activity. Transgenic mice overexpressing PPARgamma under the control of the surfactant protein C promoter had reduced expression of COX-2 in type II cells and were protected against developing lung tumors in a chemical carcinogenesis model. These data indicate that high levels of PGE(2) as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPARgamma are mediated in part through blocking this pathway.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Culture Media; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Fluorescent Antibody Technique, Indirect; Humans; Luciferases; Lung Neoplasms; Mice; Mice, Mutant Strains; Mice, Transgenic; Neoplasms, Experimental; NF-kappa B; Organ Culture Techniques; PPAR gamma; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Sulindac; Transfection; Transgenes

Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. Treatment of cancer cells with HDAC blockers, such as suberoylanilide hydroxamic acid (SAHA), leads to the activation of apoptosis-promoting genes. To enhance proapoptotic efficiency, SAHA has been used in conjunction with radiation, kinase inhibitors, and cytotoxic drugs. In the present study, we show that at the suboptimal dose of 250 muM, sulindac [2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]-acetic acid] significantly enhances SAHA-induced growth suppression and apoptosis of A549 human non-small cell lung cancer cells, primarily via enhanced collapse of the mitochondrial membrane potential, release of cytochrome c, and caspase activation. Furthermore, sulindac/SAHA cotreatment induced marked down-regulation of survivin at both the mRNA and protein levels and stimulated the production of reactive oxygen species (ROS), which were blocked by the antioxidant N-acetyl-l-cysteine. Overexpression of survivin was associated with reduced sulindac/SAHA-induced apoptosis of A549 cells, whereas suppression of survivin levels with antisense oligonucleotides or small interfering RNA further sensitized cells to sulindac/SAHA-induced cell death. Our results collectively demonstrate that sulindac/SAHA-induced apoptosis is mediated by ROS-dependent down-regulation of survivin in lung cancer cells.

Topics: Annexin A5; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Survival; Drug Synergism; Enzyme Inhibitors; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indicators and Reagents; Lung Neoplasms; Membrane Potential, Mitochondrial; Propidium; Sulindac; Tumor Cells, Cultured; Vorinostat

In the present study, we show that a combination of sulindac and arsenic trioxide (ATO) induces more extensive apoptosis than either drug alone in H1299 human non-small cell lung carcinoma (NSCLC) cells. Treatment with sulindac/ATO triggered three major apoptotic signaling events, namely, collapse of the mitochondrial membrane potential, release of cytochrome c, and activation of caspases. Furthermore, the sulindac/ATO combination induced reactive oxygen species (ROS) generation, and the antioxidant, N-acetyl-L-cysteine, blocked this apoptotic signaling. The c-Jun NH(2)-terminal kinase (JNK) was activated downstream of ROS production in H1299 cells. Blockage of JNK by pretreatment with SP600125, a pharmacological inhibitor, or transfection with dominant-negative (DN) JNK1 vectors abrogated sulindac/ATO-induced apoptosis, as evident from the disruption of caspase activation. Interestingly, a slower migrating Bcl-xL band was observed on immunoblots after treatment of cells with sulindac/ATO. The band was absent upon the treatment of cell lysates with lambda protein phosphatase. Moreover, confocal microscopy findings disclose that active JNK translocates to mitochondria. Treatment with SP600125 and transfection with DN-JNK blocked Bcl-xL phosphorylation, suggesting that JNK plays an important role in sulindac/ATO-induced Bcl-xL phosphorylation. In conclusion, in H1299 human NSCLC cells, sulindac and ATO synergistically induce a high degree of apoptosis, which is mediated by the ROS-dependent JNK activation pathway via Bcl-xL phosphorylation.

Topics: Acetylcysteine; Apoptosis; Arsenic Trioxide; Arsenicals; bcl-X Protein; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Drug Synergism; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Oxides; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Sulindac

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Caspases; Cell Division; Docetaxel; Female; Humans; In Situ Nick-End Labeling; Keratins; Ki-67 Antigen; Lung Neoplasms; Poly(ADP-ribose) Polymerases; Rats; Rats, Nude; Sulindac; Survival Rate; Taxoids; Tumor Cells, Cultured

Programmed cell death (apoptosis) is induced by certain anticancer therapies, and resistance to apoptosis is a major mechanism by which tumors evade these therapies. The transcription factor nuclear factor (NF)-kappaB, which is frequently activated by treatment of cancer cells with different chemotherapeutic agents, promotes cell survival, whereas its inhibition leads to enhanced apoptosis. Recently, sulindac and other nonsteroidal anti-inflammatory drugs have been shown to inhibit tumor necrosis factor (TNF)-alpha-mediated NF-kappaB activation. Here, we demonstrate that treatment of the non-small cell lung carcinoma cells NCI-H157 and NCI-H1299 with sulindac greatly enhances TNF-alpha-mediated apoptosis. We further show that sulindac inhibits TNF-alpha-mediated activation of NF-kappaB DNA binding and nuclear translocation of NF-kappaB. These results suggest that sulindac and other nonsteroidal anti-inflammatory drug inhibitors of NF-kappaB activation may serve as useful agents in cancer chemotherapy.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Caspases; Cell Nucleus; Cell Survival; Dose-Response Relationship, Drug; In Situ Nick-End Labeling; Lung Neoplasms; Microscopy, Fluorescence; NF-kappa B; Sulindac; Time Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However, the 5-year survival remains poor, and few patients experience a complete remission. In this report, we evaluated the effects of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth of the human non-small cell lung cancer cell line A549 in vitro and in vivo. Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the fraction of cells in the G(1) phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel increased the fraction of cells in the S phase from 17% to 19%, and 10 nM docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12-24 h after incubation. The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G(1) accumulation induced by exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%). The IC(50) for in vitro growth inhibition by exisulind alone was approximately 200 microM and 2.5 nM for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549 orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases, and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel significantly prolonged survival (P = < 0.0004), inhibited tumor growth and metastases (P = < 0.0001), and increased apoptosis (P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Division; Docetaxel; Drug Administration Schedule; Female; Humans; In Situ Nick-End Labeling; Lung Neoplasms; Mediastinal Neoplasms; Neoplasms, Experimental; Paclitaxel; Rats; Rats, Nude; Sulindac; Survival Rate; Taxoids; Tetrazolium Salts; Thiazoles