Eiro Tsubura

Arachidonic acid-induced chemiluminescence of human polymorphonuclear leukocytes

Abstract When human polymorphonuclear leukocytes were incubated with arachidonic acid, a rapid light emission was observed which reached a maximum within 2 min. The magnitude of chemiluminescence depended on the number of polymorphonuclear leukocytes and the concentration of arachidonic acid. The light emission was inhibited by about 40% or 70% by 100 μM 3-amino-1-( m -(trifluromethyl)-phenyl)-2-pyrazoline (BW755C) or 100 μM nordihydroguaiaretic acid as lipoxygenase inhibitors. In contrast, 100 μM indomethacin, a cyclooxygenase inhibitor, had no effect. These results suggested a pivotal role of the lipoxygenase pathway rather than the cyclooxygenase pathway in the light emission.

Inhibition of the arrest of hematogenously disseminated tumor cells

SummaryMost metastases in patients occur as a result of hematogenous dissemination of tumor cells (1–3). This process of metastasis is complex and consists of several steps, foremost of which is the arrest of circulating emboli in capillary beds and the formation of a thrombus at that site (4–5). Thrombus formation in the metastasis of human cancer was described first by Billroth in 1878. It was reported that the organization of tumor cell emboli, and the subsequent penetration of tumor cells into the capillary wall, was the first stage of metastasis. Since then, many investigations and observations have been made clinically as well as experimentally to clarify the process (or mechanisms) of tumor cell arrest and how to inhibit it.Coagulative and fibrinolytic pathways were believed to have a main role in thrombus formation (6, 7). However, other factors responsible for the relationship between tumor cells and the host must be also considered.Elegant and extensive studies by Fidler and Kripke (8) demonstrated that development of metastasis is not a random process, but a selection process of specialized subpopulations of highly metastatic cells within the primary tumors. Biochemical constituents and ionic properties on cell surfaces, deformability or locomotive activities of tumor cells, as well as thrombo-plastic-fibrinolytic activities, are also important factors determining the arrest patterns of circulating tumor cells. On the other hand, host defense factors against tumor cells in the bloodstream have been attracting much attention recently in tumor immunology. Host defense factors relating the arrest of tumor cells to the establishment of metastatic foci seemed difficult to define, since many studies showed contradictory data concerning the influence of immune response on tumor cell arrest (9, 10). Hemodynamic abnormality may also influence the arrest of tumor cells in the circulation (5). Hypercoagulability induced from host tissues is greatly associated with the arrest patterns (11, 12). Platelet activities might affect thrombus formation (7, 13). Nevertheless, exact explanations of the process or mechanisms inhibiting or enhancing the arrest of tumor cells after hematogenous dissemination have not been obtained. In any event, for cancer treatment, it is important to determine which substances inhibit the arrest of circulating tumor cells and how to prevent hematogenous metastasis.In this review, we will focus upon coagulative and fibrinolytic processes and then upon substances that inhibit the arrest of circulating tumor cells. Furthermore, some comments on the possible clinical applications of inhibitory substances for prevention of cancer metastasis are added.

Activation of antitumor properties in alveolar macrophages from protein-calorie malnourished rats

SummaryProtein-calorie malnutrition (PCM) was induced by feeding male F344 rats on a 5% casein diet for 7 weeks. At appropriate times, rats from control (20% casein diet) and PCM groups were killed and alveolar macrophages (AM) were obtained by bronchoalveolar lavage. The functional integrity of the AM was determined by measuring their ability to become tumoricidal on treatment with macrophage activators, such as muramyl dipeptide (MDP) or multilamellar liposomes containing MDP or its lipophilic analog, MTP-PE. After 5 and 7 weeks, the numbers of lavaged AM per gram body weight of rats were much higher in the PCM group than in the control group. In week 3, AM from the PCM group showed spontaneous tumoricidal activity against syngeneic tumor cells, but in weeks 5 and 7 they did not. However, AM from PCM rats behaved the same way as controls in their response to activation stimuli in vitro with multilamellar liposomes containing synthetic MDP or MTP-PE.These data show that PCM affects the number of AM, but that AM from rats in a state of PCM become tumoricidal in response to activation stimuli in vitro.

Activation by a new synthetic acyltripeptide and its analogs entrapped in liposomes of rat alveolar macrophages to the tumor cytotoxic state

SummaryFK-565 (heptanoyl-γ-d-Glu-(l-meso-a, ε-A2pm (l)-d-AlaOH) is a synthetic acyltripeptide closely resembling cell wall peptidoglycan peptides of Streptomyces in structure. Alveolar macrophages (AM) lavaged from lungs of F344 rats were activated by in vitro treatment with FK-565 and its derivatives at concentrations of 1–50 μg/ml medium, and the activated AM killed syngeneic mammary adenocarcinoma cells. When FK-565 and related compounds were encapsulated in multilamellar (MLV) liposomes composed of phosphatidyl-choline and phosphatidylserine, dose-response experiments showed that they were about 800 times more effective than the free compounds in activating AM. Liposome-encapsulated FK-565 and its analogs caused significant activation of AM within 4 h. These data indicated that acyltripeptide and its analogs encapsulated in liposomes are more efficient than the free compounds in rendering AM tumoricidal.

Effect of a thymic factor, thymostimulin, on growth and pulmonary metastases of Lewis lung carcinoma

SummaryThe antitumor and antimetastatic activities of a thymic factor, thymostimulin (TP-1), with or without cyclophosphamide (CPA) were examined in C57BL/6 mice inoculated with Lewis lung carcinoma (3LL).Tumor growth was followed by determining the tumor diameter after tumor implantation. TP-1 given to mice every 2 days after tumor implantation significantly inhibited tumor growth without affecting the survival rate.For induction of spontaneous pulmonary metastases, 3LL cells were implanted into the footpads of mice, and the implanted tumor was removed on day 9. The antimetastatic effect of TP-1 on pulmonary metastases after removal of the primary tumor was evaluated by counting the number of pulmonary surface nodules. TP-1 showed antimetastatic activity depending on its time of administration and dose. Combined therapy with TP-1 plus CPA significantly prolonged the survival of mice with pulmonary metastases.The cytolytic activities of spleen cells on 3LL cells were enhanced in mice treated with TP-1 and/or CPA and the cytolytic activity of nonadherent spleen cells, the T-cell population, was enhanced.The role of cytolytic spleen cells in inhibiting and preventing metastases was discussed.

Characteristics of the cellular composition, especially the lymphocyte sub‐populations of bronchoalveolar lavage fluid from patients with summer‐type hypersensitivity pneumonitis

The pathogenesis of summer‐type hypersensitivity pneumonitis, which often occurs in Japan, was examined by analysing the cell profile, especially the lymphocyte sub‐populations, of bronchoalveolar lavage fluid from these patients: twenty‐two normal volunteers and fourteen patients with localized lung cancer as controls. Lymphocyte sub‐populations were determined by the micro‐testplate method. In the bronchial fluid of the summer hypersensitivity group, the total cell number was much higher (five to ten times) than in the control groups, and the percentage of lymphocytes reached 84‐2 + 5.1 (mean + s.e. mean); the percentage of T lymphocytes was significantly increased (95.6 + 1.0), but that of B lymphocytes (3.2 + 0.6) was similar to that of the control groups, though the absolute numbers of B and T lymphocytes were higher than in the control groups. In the peripheral blood of the summer hypersensitivity group, the percentage of B lymphocytes was significantly higher than that found in the normal volunteers, but that of T lymphocytes was not increased. Cellular changes in bronchial fluid were more evident than changes seen by X‐ray examination and are considered to be a good parameter of the severity of hypersensitivity pneumonitis. It is considered that cell‐mediated immunity as well as the Arthus reaction may be intimately related to the pathogenesis of summer‐type hypersensitivity pneumonitis.

Triglyceride metabolism in the lung.

Experiments were carried out to examine whether the lung acts as a depot for circulating lipid, especially that absorbed from the intestine. When 0.5 ml of triolein was administered orally to rats, the triglyceride content of the lung increased 2-3 hr later, but its increase in the lungs 2-3 hr later was only of about 1/10 of that in the liver. In the fed state the triglyceride content of the lung was only about 1/8 of that of the liver. When [3H]palmitic acid was administered orally to mice its uptake by the lung 1 and 2 hr later was 1/25-40 of that by the liver. In the lung, it was incorporated into phospholipid more than into triglyceride, but in the liver it was predominatly incorporated into triglyceride. Most of the lipase activity in both the microsomal and soluble fractions of rat lung appeared to be due to lipoprotein lipase. Fasting did not decrease the lipoprotein lipase activity in either fraction. It was concluded that the lung is not important in removal of triglyceride from the blood, even during fat absorption from the intestine, and that the lung takes up circulating lipid for its own metabolism rather than for storage.

A case of portal hypertension of vinyl chloride worker

塩化ビニール・モノマーの暴露が関係していると思われる門脈圧亢進症の1例について報告する. 症例は38歳の男性で,18年9カ月間にわたり塩化ビニール製造作業に従事していたが,脾腫,食道および胃の静脈瘤を伴う門脈圧亢進症と診断され脾摘出術および食道離断術を受けた.術前の検査では血小板数の減少,ICGおよびBSPによる色素排泄能の障害が認められたが,GOT,GPT,およびアルカリフォスファターゼ値は正常であった.肝の組織学的検査では門脈域の線維化が著しく,小葉間におよぶ線維性の隔壁があり,類洞内皮細胞の僅かな増加がみられた.摘出脾では著明な慢性うっ血像を示し,脾洞の増生,髄索および血管周囲の線維化がみられた.患者は術後8カ月目に絞拒性腸閉塞で同部の切除術を受けたが,術後に腎不全および汎発性腹膜炎で死亡した.

Effects of Cytotoxic Drugs and/or Corticosteroids on Peripheral Leukocytes

The myeloperoxidase (MPO) activity of patients treated with cytotoxic drugs and/or corticosteroids was lower than that of healthy controls. Cyclophosphamide decreases the number of leukocytes without affecting the MPO activity per cell. At the same dose of anti-inflammatory potency, dexamethasone caused more decrease than other corticosteroids in the MPO level, nitro-blue tetrazolium (NET) and number of polymorphonuclear leukocytes (PMN). However, on successive daily treatment with dexamethasone for 7 days, the MPO level and NET returned to normal, although phagocytosis of Candida by PMN diminished to about 60 % of the normal level. Pretreatment of rats with heat-killed Candida albicans protected the functions of PMN against dexamethasone.