thromboxane-b2 and Lung-Neoplasms

We measured serum levels of soluble (s) P-selectin and thromboxane B2 (TxB2) in patients with lung cancer treated with gefitinib, and investigated the effect of low-dose aspirin on some adverse effects of gefitinib. The serum levels of sP-selectin and TxB2 increased significantly in all patients who received gefitinib for 2 weeks. Forty patients were recruited, and 28 received gefitinib without low-dose aspirin (Group 1) and 12 were co-administered low-dose aspirin (Group 2). In Group 2, the frequency of adverse events, skin rash and diarrhea was evidently reduced by the low-dose aspirin therapy, despite having shown no remarkable change in gefitinib responsiveness between both groups. In one of the 12 patients in Group 2, aspirin therapy was suspended due to the occurrence of nasal bleeding. Four days after treatment suspension, she developed a skin lesion in her finger. However, the skin lesion improved after re-administration of aspirin without any other medications. After treatment, TxB2 significantly decreased, but not sP-selectin. These results suggest that one of the mechanisms causing gefitinib-related adverse effects depends on platelet activation. Administration of gefitinib with low-dose aspirin to lung cancer patients may prevent the development of gefitinib-related complications.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Female; Gefitinib; Humans; Lung Neoplasms; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Quinazolines; Thromboxane B2

To explore the role of hypercoagulation in the metastasis of carcinoma.. The effect of Tetramethylpyrazine (TTMP) on platelet functions among the 25 advanced cases of lung carcinoma, and 26 matched control subjects were investigated in the study. Their ages varied from 31-86 years (mean 58.2) in lung carcinoma group (13 male, 12 female) and 36 to 61 (mean 52.9) in the control group (16 male, 10 female). The pathologic types were as follows: 7 cases of squamous cell cancer, 12 adenocarcinoma, 2 small cell carcinoma and 4 undistinguished type. The TNM stage revealed 14 cases in stage IIIa, 3 in stage IIIb and 8 in stage IV. The site of metastasis included mediastinal lymph node, pleura, supraclavicular lymph node, brain, spine, costa, skin and pericardium. The levels of plasma TXB2, 6-keto-PGF1 alpha, VIII:C, vWF, AT-III:a, AT-III:Ag, Fg and blood PAdT, PAgT were measured before and after the intravenous infusion of 80 mg TTMP in patients with lung carcinoma.. The levels of TXB2, 6-keto-PGF1 alpha, VIII:C, vWF and Fg in lung carcinoma group were significantly elevated, while the levels of PAdT was greatly decreased, compared with the control group, no significant differences in levels of PAgT, AT-III:a and AT-III:Ag were found between the two groups. After the infusion of TTMP the levels of PAdT, PagT, VIII:C, dWF and Fg were decreased significantly, while TXB2, 6-keto-PGF1 alpha, AT-III:a and AT-III:Ag remained unchanged.. TTMP inhibits the adhesion and aggregatory functions of blood platelet and the activity of coagulation factors. It might be one of the mechanisms of TTMP's antimetastasis of lung carcinoma.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazines; Thromboxane B2

Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with angiogenesis and poor outcome. TXS has been identified as a potential therapeutic target in NSCLC. This study examines a link between TXS expression, angiogenesis, and survival in NSCLC.. TXS and VEGF metabolite levels were measured in NSCLC serum samples (n=46) by EIA. TXB2 levels were correlated with VEGF. A 204-patient TMA was stained for TXS, VEGF, and CD-31 expression. Expression was correlated with a range of clinical parameters, including overall survival. TXS expression was correlated with VEGF and CD-31. Stable TXS clones were generated and the effect of overexpression on tumor growth and angiogenesis markers was examined in-vitro and in-vivo (xenograft mouse model).. Serum TXB2 levels were correlated with VEGF (p<0.05). TXS and VEGF were expressed to a varying degree in NSCLC tissue. TXS was associated with VEGF (p<0.0001) and microvessel density (CD-31; p<0.05). TXS and VEGF expression levels were higher in adenocarcinoma (p<0.0001) and female patients (p<0.05). Stable overexpression of TXS increased VEGF secretion in-vitro. While no significant association with patient survival was observed for either TXS or VEGF in our patient cohort, TXS overexpression significantly (p<0.05) increased tumor growth in-vivo. TXS overexpression was also associated with higher levels of VEGF, microvessel density, and reduced apoptosis in xenograft tumors.. TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neovascularization, Pathologic; Thromboxane B2; Thromboxane-A Synthase; Tissue Array Analysis; Vascular Endothelial Growth Factor A

Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease.. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression.. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis.. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.

Topics: Adenocarcinoma; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lung Neoplasms; Male; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane B2; Thromboxane-A Synthase; Tissue Array Analysis

Topics: Aged; Aspirin; Dose-Response Relationship, Drug; Erlotinib Hydrochloride; Exanthema; Female; Humans; Lung Neoplasms; Male; Platelet Activation; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Quinazolines; Thromboxane B2; Treatment Outcome

There is little information regarding simultaneous investigations of thromboxane A(2) (TXA(2)) lipid peroxidation and Bcl-2, three cancer-related agents, and analyses of their relationships in lung cancer. The present study was to study thromboxane B(2) (TXB(2)), a stable metabolite of TXA(2), lipid peroxidation and Bcl-2 expression in 52 non-small cell lung carcinoma (NSCLC) tissue samples. The level of thiobarbituric acid reactive substances (TBARS), an index for lipid peroxidation was significantly increased in the lung tumor tissues, compared with non-tumor tissues. TXB(2) was much higher in the tumor tissues than non-tumor tissues. Interestingly, the concentration of TXB(2) in samples from those who smoked was higher than that from those who did not smoke. The expression of Bcl-2 was significantly elevated in the tumor tissues, compared to the non-tumor tissues. There was also a positive correlation between TXB(2) and TBARS in tumor tissues; advanced stage cancers had higher levels of TXB(2). This finding supports the idea that TXB(2) may have a role in promoting tumor growth. In conclusion, our study demonstrates that the production of TXB(2) is increased in lung tumor tissues and that such an increase can result in lipid peroxidation which may be met by an elevation in Bcl-2 expression.

Topics: Carcinoma, Non-Small-Cell Lung; Female; Humans; Lipid Peroxidation; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Proto-Oncogene Proteins c-bcl-2; Thiobarbituric Acid Reactive Substances; Thromboxane B2

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

In order to investigate the possible mechanisms underlying platelet functional changes in patients affected by neoplasms, platelet lipid composition, plasma beta-thromboglobulin (Beta-TG) and serum thromboxane B2 (TXB2) were investigated in 16 male patients affected by pulmonary carcinoma and in 16 comparable control subjects. In patients high levels of plasma Beta-TG (67 +/- 9 versus controls 14 +/- 4 ng/ml, p < 0.001) and serum TXB2 (434 +/- 56 versus 223 +/- 48 ng/ml, p < 0.001) were observed. Also platelet lipid composition was found altered in patients with respect to controls (lower percent levels in n-3 fatty acids and in linoleic acid esterified in the main platelet phospholipid fractions: at least p < 0.05). These results indicate that in vivo platelet activation is detectable in neoplastic patients and it is associated with alterations in platelet lipid composition. In the light of the important role played by membrane lipids in platelet functions related to thrombosis and haemostasis we conclude that platelet lipid changes could cooperate in platelet activation and increased thrombotic risk so frequently observed in neoplastic disease.

Topics: Adult; beta-Thromboglobulin; Blood Platelets; Carcinoma, Squamous Cell; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Linoleic Acid; Linoleic Acids; Lipids; Lung Neoplasms; Male; Platelet Activation; Platelet Factor 4; Thromboxane B2

108 cases of advanced non-small cell lung cancer (NSCLC) with Qi deficiency and blood stasis syndrome (QDBS) had been studied in this paper. It has been found that: (1) QDBS existed commonly in 60.2% of NSCLC patients. (2) QDBS patients had lowered immune function and blood hypercoagulating function, as compared with healthy persons. (3) The abnormal change of immunological indexes such as TC subgroup. TXB2, 6-keto-PGF1 alpha, fibrinogen and plasmin activity as well as hemorheological indices are important pathophysiological manifestation of QDBS. Thus, the principle of supplementing Qi and activating blood circulation combined with reducing phlegm and resolving masses should be emphasized in future research.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Carcinoma, Non-Small-Cell Lung; Diagnosis, Differential; Female; Fibrinogen; Humans; Immunity, Cellular; Lung Neoplasms; Male; Medicine, Chinese Traditional; Middle Aged; T-Lymphocyte Subsets; Thromboxane B2

Polyactin A (PAA) is a home-made immunomodulator, isolated from submerged culture broths of alpha-hemolytic streptococci. The effect of PAA on the metastasis of B16-F10 melanoma cells in the syngeneic C57BL/6J mice and its antimetastatic mechanism have been studied. The results showed that: PAA inhibited the experimental pulmonary metastasis nodules at a dose of 100 mg.kg-1.d-1 for 18 d. The number of pulmonary metastasis nodules were significantly decreased from 137 to 95 as compared with those in the control; The plasma concentration of TXB2 in B16 bearing mice was higher than that in normal mice. After treatment with PAA, a decreased content of TXB2 and 6-keto-PGF1 alpha was found without change of the ratio TXB2 to 6-keto-PGF1 alpha. The cellular immunities were evidently decreased in the B16 bearing mice. The restoration of lymphocyte proliferation response and augmentation of the NK cell activity of the splenocytes were found in vivo in normal mice and B16 bearing mice after treated with PAA. PAA was also shown to antagonize the suppressing effect of cyclophosphamide on murine NK cells; PAA at the concentration of 10-5000 micrograms.ml-1 was found to inhibit the biosynthesis of DNA, RNA and protein in the B16-F10 melanoma cells to different degrees and the effect was dose-dependent. It is evident that PAA is effective in preventing the pulmonary metastasis of B16-F10 melanoma and the antimetastatic action may be related not only to promoting the effect the antitumor immunities, but also to inhibiting the growth of B16-F10 melanoma cells.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Glycopeptides; Immunologic Factors; Killer Cells, Natural; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Thromboxane B2

Topics: Animals; Cell Division; Dinoprostone; Female; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Metastasis; Prostaglandins; Thromboxane B2

Detectable levels (greater than or equal to 0.2 pmol/10(6) cells) of one or more prostanoid species resultant to calcium ionophore A23187-induced biosynthesis from endogenous arachidonic acid were distributed in 28 cell lines derived from different histological classes of lung tumors as follows: large cell undifferentiated carcinoma (3 of 3 cell lines); adenosquamous carcinoma (1 of 2 cell lines); squamous cell carcinoma (0 of 2 cell lines); adenocarcinoma (9 of 10 cell lines); bronchioloalveolar cell carcinoma (2 of 2 cell lines); and small cell carcinoma (1 of 9 cell lines). Using the mean levels of 9 alpha,11 beta-prostaglandin F2, prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2, thromboxane B2 and 6-keto-prostaglandin F1 alpha as an index of prostaglandin H (PGH) synthase activity, the distribution in cell lines representative of the different histological classes of human lung tumors exhibiting PGH synthase activity exceeding mean values greater than or equal to 2 pmol/10(6) cells was as follows: large cell undifferentiated carcinoma (3 of 3 cell lines), adenosquamous carcinoma (1 of 2 cell lines), adenocarcinoma (8 of 10) cell lines), bronchioloalveolar cell carcinoma (2 of 2 cell lines) and small cell carcinoma (0 of 9 cell lines). Three different prostanoid species accumulated to mean levels greater than or equal to 2 pmol/10(6) cells. Prostaglandin E2 levels exceeded 2 pmol/10(6) cells in 14 of the 16 cell lines in which this prostanoid accumulated to detectable levels. Cumulative levels of prostaglandin F2 alpha exceeded 2 pmol/10(6) cells in 9 of the 15 cell lines in which prostaglandin F2 alpha reached detectable levels. Detectable levels of thromboxane B2 were observed in five cell lines with thromboxane B2 accumulation exceeding 2 pmol/10(6) cells in two of the five cell lines. 9 alpha,11 beta-prostaglandin F2 and 6-keto-prostaglandin F1 alpha accumulated to detectable levels in the culture medium of one cell line, while prostaglandin D2 accumulation to detectable levels was observed in two cell lines. Stimulation of cultured human lung tumor cells exhibiting PGH synthase activity greater than or equal to 2 pmol/10(6) cells in the presence of 10(-5) M exogenous arachidonic acid resulted in a 2- to 4-fold increase in the accumulation of individual prostanoids, while the inclusion of a 10(-5) M exogenous concentration of arachidonic acid failed to stimulate detectable prostanoid production in human lung tumor cells in which PGH synt

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line; Humans; Kinetics; Lung Neoplasms; Prostaglandins; Thromboxane B2; Tumor Cells, Cultured

Eicosanoid synthesis by alveolar macrophages (AM), harvested from tumor bearing animals, was measured after tumor inoculation in rats treated with or without carrageenan (carra), an immunomodulating agent. After incubation of the cells with [14]C-arachidonic acid and the Ca-ionophore A23187, samples were measured by high pressure liquid chromatography (HPLC). From the HPLC profiles the lypoxygenase products, 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, and leukotriene-B4 (LTB4) were determined as well as the cyclooxygenase products, prostaglandin (PG)E2, PGF2 alpha and TXB2. After tumor inoculation AM-synthesis of lipoxygenase products tended to increase to values twice those of the base line values, whereas cyclooxygenase products showed subnormal values. In the non treated animals, 10 days after tumor inoculation, statistically significant increases in 12- and 15-HETE, LTB4 and PGE2 were observed when compared with carra treated animals. Later measurements did not show these differences in AM metabolism. AM metabolism was (negatively) correlated with the number of macrophages, which was particularly evident in the correlation with 12-HETE synthesis.

Topics: Animals; Arachidonic Acids; Carrageenan; Chromatography, High Pressure Liquid; Dinoprost; Dinoprostone; Drug Implants; Female; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lung Neoplasms; Macrophages; Mammary Neoplasms, Experimental; Prostaglandins; Pulmonary Alveoli; Rats; Rats, Inbred BN; Thromboxane B2; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Female; Humans; Lipid Peroxides; Lung Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Thromboxane B2

Lewis lung primary carcinomas have been extracted for eicosanoids, and the findings examined in relation to lung metastases. The order of the 5 compounds measured was PGE2 greater than PGE1 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than TXB2. On the basis of the observation that the balance of PGI2 and TXA2 is altered in metastasis (Honn et al., 1983), the effects of Nafazatrom, a PGI2 enhancing agent, and imidazole, a thromboxane synthetase inhibitor, were tested. The experimental approach taken was to study spontaneous lung metastases after removal of the primary tumour at 13 days after tumour cell inoculation. Both Nafazatrom and imidazole decreased the lung weight when given during the period either before or after the excision of the primary tumour. There was a general trend toward an increase in the number of small lung nodules (greater than 2 mm) and a decrease in large lung nodules (greater than 2 mm) as a result of the chemotherapy. Mean survival time of the mice was significantly different among the five groups, with the mice surviving the longest in the group treated with Nafazatrom after the excision of the primary tumour.

Topics: Animals; Body Weight; Carcinoma; Imidazoles; Lung; Lung Neoplasms; Mice; Neoplasm Metastasis; Organ Size; Prostaglandins; Prostaglandins E; Prostaglandins F; Pyrazoles; Pyrazolones; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Epoprostenol; Female; Humans; Lung Neoplasms; Male; Middle Aged; Platelet Aggregation; Pneumonectomy; Thromboxane B2; Thromboxanes