iloprost and Lung-Neoplasms

Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analog) with placebo in high-risk subjects showed improvement in bronchial histology in former, but not current, smokers. This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoint and predictive biomarkers to incorporate into chemoprevention trials. Matched bronchial biopsies were obtained at baseline and at 6-month follow-up from 125 high-risk individuals who completed the trial: 31/29 and 37/28 current/former smokers in the iloprost and placebo arm, respectively. We analyzed the expression of 14 selected miRNAs by Real Time PCR in 496 biopsies. The expression of seven miRNAs was significantly correlated with histology at baseline. The expression of miR-34c was inversely correlated with histology at baseline (P < 0.0001) and with change in histology at follow-up (P = 0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was upregulated at baseline (P < 0.0001) and downregulated after treatment with iloprost (P = 0.0023). No miRNA at baseline reliably predicted a response to iloprost. No biomarker predictive of response to iloprost was found. MiR-34c was inversely correlated with baseline histology and with histology changes. Mir-34c changes at follow-up could be used as a quantitative biomarker that parallels histologic response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies.

Topics: Administration, Oral; Antineoplastic Agents; Biomarkers, Tumor; Bronchi; Case-Control Studies; Chemoprevention; Humans; Iloprost; Lung Neoplasms; MicroRNAs; Placebos; Smoking

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.

Topics: Biopsy; Bronchi; Bronchoscopy; Double-Blind Method; Female; Follow-Up Studies; Humans; Hyperplasia; Iloprost; Lung Neoplasms; Male; Middle Aged; Smoking; Sputum; Treatment Outcome; United States; Vasodilator Agents

Lung cancer chemoprevention is critical to addressing cancer burden in high-risk populations. Chemoprevention clinical trials rely on data from preclinical models; however, in vivo studies have high financial, technical, and staffing requirements. Precision cut lung slices (PCLS) provide an ex vivo model that maintains the structure and function of native tissues. This model can be used for mechanistic investigations and drug screenings and reduces the number of animals and time required to test hypotheses compared with in vivo studies. We tested the use of PCLS for chemoprevention studies, demonstrating recapitulation of in vivo models. Treatment of PCLS with the PPARγ agonizing chemoprevention agent iloprost produced similar effects on gene expression and downstream signaling as in vivo models. This occurred in both wild-type tissue and Frizzled 9 knockout tissue, a transmembrane receptor required for iloprost's preventive activity. We explored new areas of iloprost mechanisms by measuring immune and inflammation markers in PCLS tissue and media, and immune cell presence with immunofluorescence. To demonstrate the potential for drug screening, we treated PCLS with additional lung cancer chemoprevention agents and confirmed activity markers in culture. PCLS offers an intermediate step for chemoprevention research between in vitro and in vivo models that can facilitate drug screening prior to in vivo studies and support mechanistic studies with more relevant tissue environments and functions than in vitro models.. PCLS could be a new model for premalignancy and chemoprevention research, and this work evaluates the model with tissue from prevention-relevant genetic and carcinogen exposed in vivo mouse models, in addition to evaluating chemoprevention agents.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Chemoprevention; Iloprost; Lung; Lung Neoplasms; Mice

Although both preclinical and clinical studies have suggested that myo-inositol (MI) may be a safe and effective lung cancer chemopreventive agent, its efficacy is moderate. To test whether the chemopreventive agents iloprost (IL) or rapamycin enhance the lung tumor inhibitory effects of MI, A/J mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and, beginning one week after the end of NNK treatment, given MI, IL, rapamycin, MI + IL or MI + rapamycin for 17 weeks. Analyses of the number and size of tumors on the surface of the lung have indicated that MI, IL, rapamycin, MI + IL and MI + rapamycin reduced the multiplicity of NNK-induced lung tumors by 41, 34, 46, 79 and 67%, respectively, and larger tumors (lung tumors with a diameter of 1-2 or >2 mm) were absent in the MI + IL and MI + rapamycin groups. These results clearly indicated that MI + IL and MI + rapamycin are more effective than MI alone in inhibiting the formation and growth of lung tumors. Assessment of the immunomodulatory effects of the drugs showed that whereas MI + rapamycin and MI + IL increased the infiltration of lung tumors by CD4+ and CD8+ T cells, MI + rapamycin reduced the expression of the immune checkpoint protein programmed-death ligand-1 (PD-L1). Moreover, all treatments, except IL, increased apoptosis, whereas cell proliferation was markedly suppressed in all treated groups. In summary, these results suggest that IL and rapamycin could enhance the efficacy of MI in lung cancer chemoprevention trials.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Iloprost; Immunomodulation; Inositol; Lung Neoplasms; Mice; Nitrosamines; Sirolimus

Expression of Frizzled 9 (FZD9) is critical to the activity of the lung cancer chemoprevention agent and prostacyclin analogue, iloprost. FZD9 is required in lung epithelial cells for iloprost to activate peroxisome proliferator activated receptor gamma (PPARG) and related anti-tumor signaling. We aimed to investigate which miRNA regulate FZD9 in the context of cigarette smoke exposure and iloprost treatment. We found that miR-520a-5p binds the FZD9 3'UTR in lung cell lines and alters activity and expression of FZD9 downstream targets. Cigarette smoke condensate (CSC) increases expression of miR-520a-5p, while iloprost decreases expression. Cancer promoting effects of a miR-520a-5p mimic were rescued with iloprost treatment, and effects of cigarette smoke were partially rescued with a miR-520a-5p inhibitor. Here we confirm miR-520a-5p as a regulator of FZD9 activity and a mediator of CSC and iloprost effects in the lung. Targeting miR-520a-5p could be an approach to restoring FZD9 expression and improving response to iloprost lung cancer chemoprevention.

Topics: Cell Line, Tumor; Chemoprevention; Cigarette Smoking; Epithelial Cells; Frizzled Receptors; Humans; Iloprost; Lung Neoplasms; MicroRNAs; PPAR gamma; Protein Binding; Protein Domains

Mouse iloprost lung cancer chemoprevention studies typically use oral delivery. Here, we present a protocol for intranasal iloprost delivery within a urethane lung adenocarcinoma mouse model. We detail steps for intraperitoneal urethane injection in mice, followed by nine-week monitoring, intranasal iloprost treatment, and lungs harvesting for analysis. This iloprost delivery approach parallels an ongoing phase II clinical trial of inhaled iloprost for lung cancer chemoprevention. This protocol diversifies options for chemoprevention studies and offers a relevant and translatable model. For complete details on the use and execution of this protocol, please refer to Sompel et al. (2022).

Topics: Animals; Carcinogens; Chemoprevention; Disease Models, Animal; Enzyme Inhibitors; Iloprost; Lung Neoplasms; Mice; Urethane

Lung cancer is the leading cause of cancer death worldwide and global burden could be reduced through targeted application of chemoprevention. The development of squamous lung carcinoma has been linked with persistent, high-grade bronchial dysplasia. Bronchial histology improved in former smokers in a chemoprevention trial with the prostacyclin analogue iloprost. Prostacyclin acts through peroxisome proliferator-activated receptor gamma (PPARγ) to reverse epithelial to mesenchymal transition and promote anticancer signaling. We hypothesized that the prostacyclin signaling pathway and EMT could provide response markers for prostacyclin chemoprevention of lung cancer. Human bronchial epithelial cells were treated with cigarette smoke condensate (CSC) or iloprost for 2 weeks, CSC for 16 weeks, or CSC for 4 weeks followed by 4 weeks of CSC and/or iloprost, and RNA was extracted. Wild-type or prostacyclin synthase transgenic mice were exposed to 1 week of cigarette smoke or one injection of urethane, and RNA was extracted from the lungs. We measured potential markers of prostacyclin and iloprost efficacy in these models. We identified a panel of markers altered by tobacco carcinogens and inversely affected by prostacyclin, including

Topics: Animals; Anticarcinogenic Agents; Biomarkers; Bronchi; Carcinogens; Cell Line; Cytochrome P-450 Enzyme System; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoprostenol; Humans; Iloprost; Intramolecular Oxidoreductases; Lung Neoplasms; Mice; Mice, Transgenic; Neoplasms, Experimental; Nicotiana; Smoke; Tobacco Smoking; Treatment Outcome

Lung cancer remains an important target of cancer research, and accounts for most deaths of any cancer type in the United States. Chemoprevention refers to the use of agents to prevent the development of cancer in high-risk populations, often in patients with predisposing lesions. In the following, we describe our ongoing work examining the role of the eicosanoid prostacyclin in lung cancer chemoprevention. Our findings include the fact that most adenocarcinomas lose the expression of prostacyclin synthase through methylation silencing. In addition, transgenic mice with overexpression of prostacyclin synthase are protected from tumorigenesis in multiple preclinical lung cancer models. Our phase IIb clinical trial using iloprost, a prostacyclin analogue, showed the reversal of airway dysplasia in high-risk individuals. This trial represents the first to show regression of airway dysplasia from the administration of a chemoprevention agent and forms the basis for future trials in lung cancer chemoprevention.

Topics: Adenocarcinoma of Lung; Animals; Anticarcinogenic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Clinical Trials, Phase II as Topic; Cytochrome P-450 Enzyme System; Humans; Iloprost; Intramolecular Oxidoreductases; Lung Neoplasms; Mice; Molecular Targeted Therapy; Mutation; PPAR gamma; Signal Transduction; Treatment Outcome; Xenograft Model Antitumor Assays

Half of lung cancers are diagnosed in former smokers, leading to a significant treatment burden in this population. Chemoprevention in former smokers using the prostacyclin analogue iloprost reduces endobronchial dysplasia, a premalignant lung lesion. Iloprost requires the presence of the WNT receptor Frizzled 9 (Fzd9) for inhibition of transformed growth in vitro. To investigate the relationship between iloprost, cigarette smoke, and Fzd9 expression, we used human samples, mouse models, and in vitro studies. Fzd9 expression was low in human lung tumors and in progressive dysplasias. In mouse models and in vitro studies, tobacco smoke carcinogens reduced expression of Fzd9 while prostacyclin maintained or increased expression. Expression of miR-31 repressed Fzd9 expression, which was abrogated by prostacyclin. We propose a model where cigarette smoke exposure increases miR-31 expression, which leads to decreased Fzd9 expression and prevents response to iloprost. When smoke is removed miR-31 is reduced, prostacyclin can increase Fzd9 expression, and progression of dysplasia is inhibited. Fzd9 and miR-31 are candidate biomarkers for precision application of iloprost and monitoring of treatment progress. As we continue to investigate the mechanisms of prostacyclin chemoprevention and identify biomarkers for its use, we will facilitate clinical trials and speed implementation of this valuable prevention approach.

Topics: Animals; Bronchi; Cells, Cultured; Epithelial Cells; Epoprostenol; Frizzled Receptors; Gene Expression Regulation; Humans; Iloprost; Lung Neoplasms; Mice; Mice, Transgenic; MicroRNAs; Nicotiana; Smoke; Urethane

Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of β-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.

Topics: Animals; beta Catenin; Cell Line, Tumor; Cellular Senescence; Humans; Iloprost; Lung Neoplasms; Mice; Mice, Inbred C57BL; S-Phase Kinase-Associated Proteins; Signal Transduction; Tumor Suppressor Proteins; Wnt Proteins

Systemic sclerosis (SSc) is a chronic disease of unknown etiology which affects the vascular system and connective tissue. A wide series of studies showed an increased prevalence of cancer in patients with SSc than the normal population. Prostacyclin (PGI2) is an endogenously produced element that is basically synthesized by arachiodonic acid through prostacyclin synthesis in vascular system endothelial cells. Iloprost is a stable analogue of PGI2 which is used in the treatment of pulmonary arterial hypertension (PAH). In a limited number of animal models, the anti-metastatic activity of PGI2 is observed. Herein, we report iloprost treatment of a 60-year-old-woman with SSc, who lately developed PAH as a complication of her disease and lung adenocarcinoma as a co-incidence simultaneously. These two mortal complications were both treated successfully with inhaled iloprost until her death due to gastrointestinal complications of SSc.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Antihypertensive Agents; Antineoplastic Agents; Biopsy; Disease Progression; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Gastrointestinal Diseases; Humans; Hypertension, Pulmonary; Iloprost; Immunohistochemistry; Lung Neoplasms; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Scleroderma, Systemic; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

The history of lung cancer chemoprevention trials has been uniformly disappointing in that the large phase III studies showed no effect or harm in actively smoking participants, and smaller phase II studies have also been negative. In this issue of the journal (beginning on page 793), Keith and colleagues report their randomized, placebo-controlled trial of the oral prostacyclin analogue iloprost, the first trial to show an improvement in bronchial histology (i.e., regression), which occurred in former, but not current, smokers with sputum atypia. This Perspective discusses the strength of the clinical signal provided by this observation and its implications for further drug development.

Topics: Bronchi; Humans; Hyperplasia; Iloprost; Lung Neoplasms; Smoking; Vasodilator Agents

Prostanoids are bioactive lipids that interact with 7-membrane-spanning G-protein-coupled receptors on target cells to impart their biologic effects. They include prostaglandins, prostacyclin, and thromboxane. Prostanoids are widely distributed; mediate several diverse biologic effects like platelet aggregation and smooth-muscle contraction; and are known to be involved in allergies, acquired immunity, and cancer metastasis. Prostanoids have also been associated with breast and endometrial cancer promotion, and with the inhibition of melanoma. The role of prostanoids in the development of lung disease has been poorly understood. In particular, prostacyclin possesses significant anti-inflammatory and antimetastatic properties and is the main product of cyclooxygenase-2 activity in the lung. In fact, the balance of the various members of the prostanoids family, specifically the prostaglandins PGE(2) and prostacyclin (PGI(2)), seems to play an increasingly important role in the development of lung cancer. Gaining a better understanding of prostanoids and their associated pathways is critical to the future development of molecular-based and pharmaceutical treatments of lung disease.

Topics: Carcinoma, Non-Small-Cell Lung; Epoprostenol; Humans; Iloprost; Lung Neoplasms; Receptors, G-Protein-Coupled; Signal Transduction; Vasodilator Agents

The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma). Silencing of Fzd 9 blocked PPARgamma activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPARgamma and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.

Topics: Animals; Antihypertensive Agents; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Frizzled Receptors; Glycoproteins; Humans; Iloprost; Intracellular Signaling Peptides and Proteins; Luciferases; Lung Neoplasms; Mice; PPAR gamma; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured

Overexpression of prostacyclin synthase (PGIS) decreases lung tumor multiplicity in chemical- and cigarette-smoke-induced murine lung cancer models. Prostacyclin signals through a single G-protein-coupled receptor (IP), which signals through cyclic AMP. To determine the role of this receptor in lung cancer chemoprevention by prostacyclin, PGIS-overexpressing mice were crossed to mice that lack the IP receptor [IP(-/-)]. Carcinogen-induced lung tumor incidence was similar in IP(+/+), IP(+/-), and IP(-/-) mice, and overexpression of PGIS gave equal protection in all three groups, indicating that the protective effects of prostacyclin are not mediated through activation of IP. Because prostacyclin can activate members of the peroxisomal proliferator-activated receptor (PPAR) family of nuclear receptors, we examined the role of PPARgamma in the protection of prostacyclin against lung tumorigenesis. Iloprost, a stable prostacyclin analogue, activated PPARgamma in nontransformed bronchial epithelial cells and in a subset of human non-small-cell lung cancer cell lines. Iloprost-impregnated chow fed to wild-type mice resulted in elevated lung macrophages and decreased lung tumor formation. Transgenic animals with lung-specific PPARgamma overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARgamma is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Epoprostenol; Genotype; Humans; Iloprost; Intramolecular Oxidoreductases; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Transgenic; PPAR gamma; Rats; Receptors, Epoprostenol; Respiratory Mucosa; Tumor Cells, Cultured

The use of doxorubicin (DOX) as a chemotherapeutic agent is limited by cardiac injury. Iloprost, a stable synthetic analogue of prostacyclin, has previously been shown to protect against DOX-induced cardiomyocyte injury in vitro. Here, we addressed whether iloprost is cardioprotective in vivo and whether it compromises the anti-tumour efficacy of DOX.. Lewis Lung Carcinoma cells were implanted subcutaneously in the flank of C57BL/6 mice. DOX treatment was commenced from when tumours became visible. Iloprost was administered from prior to DOX treatment until sacrifice. Echocardiography and invasive haemodynamic measurements were performed immediately before sacrifice. As expected, DOX induced cardiac cell apoptosis and cardiac dysfunction, both of which were attenuated by iloprost. Also, iloprost alone had no effect on tumor growth and indeed, did not alter the DOX-induced suppression of this growth.. In a murine model, iloprost attenuated the acute cardiac injury and dysfunction induced by DOX therapy without compromising its chemotherapeutic effect.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Lewis Lung; Cardiomyopathies; Cell Division; Doxorubicin; Drug Interactions; Iloprost; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Neoplasm Transplantation; Tumor Cells, Cultured

We have isolated and characterized a novel human and rat organic anion transporter subtype, OATP-D. The isolated cDNA from human brain encodes a polypeptide of 710 amino acids (Mr 76,534) with 12 predicted transmembrane domains. The rat clone encodes 710 amino acids (Mr 76,821) with 97.6% amino acid sequence homology with human OATP-D. Human and rat OATP-D have moderate amino acid sequence homology with LST-l/rlst-1, the rat oatp family, the prostaglandin transporter, and moatl/MOAT1/KIAA0880/OATP-B. Phylogenetic tree analysis revealed that OATP-D is branched in a different position from all known organic anion transporters. OATP-D transports prostaglandin E1 (Km 48.5 nM), prostaglandin E2 (Km 55.5 nM), and prostaglandin F2,, suggesting that, functionally, OATP-D encodes a protein that has similar characteristics to those of the prostaglandin transporter. Rat OATP-D also transports prostaglandins. The expression pattern of OATP-D mRNA was abundant mainly in the heart, testis, brain, and some cancer cells. Immunohistochemical analysis further revealed that rat OATP-D is widely expressed in the vascular, renal, and reproductive system at the protein level. These results suggest that OATP-D plays an important role in translocating prostaglandins in specialized tissues and cells.

Topics: Alprostadil; Amino Acid Sequence; Animals; Anions; Blotting, Northern; Brain Chemistry; Burkitt Lymphoma; Dinoprostone; DNA, Complementary; HeLa Cells; HL-60 Cells; Humans; K562 Cells; Leukemia, Lymphoid; Lung Neoplasms; Melanoma; Molecular Sequence Data; Oocytes; Organic Anion Transporters; Rats; RNA, Messenger; Xenopus laevis

The stable prostacyclin (PGI2) analogue, iloprost, is a potent inhibitor of both tumor cell-induced platelet aggregation and of experimental metastasis in mice. To explore possible mechanisms of antimetastatic effect of iloprost, we measured the effect of this drug on both platelet aggregation and immunocompetence in the mouse. Iloprost (4 x 10(-8) M) inhibited platelet aggregation as induced by a mixture of collagen and epinephrine for at least 180 minutes of incubation, and completely reversed platelet aggregation when added during the second wave of aggregation. In addition, aggregation of platelets obtained from iloprost-treated mice (0.2 mg/kg) was completely inhibited for at least 90 minutes of incubation. Moreover, iloprost pretreatment in vivo counteracted tumor cell-induced thrombocytopenia. Thus, mouse platelets were equally sensitive to the inhibitory effect of iloprost on aggregation as platelets of other species including humans. Effects of iloprost on parameters of host immunocompetence that may influence tumor growth and metastasis formation were also evaluated. Iloprost treatment increased significantly macrophage cytostasis to tumor cells, natural killer (NK) lytic activity of spleen cells and T-cell mediated cytotoxicity ex vivo. These results suggested that the antimetastatic effect of iloprost in the mouse may be attributable to multiple mechanisms including inhibition of platelet aggregation and stimulation of certain host immune functions.

Topics: Aging; Animals; Cell Line; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Epoprostenol; Female; Iloprost; In Vitro Techniques; Killer Cells, Natural; Kinetics; Lung; Lung Neoplasms; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Platelet Aggregation; Platelet Aggregation Inhibitors; Reference Values; T-Lymphocytes, Cytotoxic