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Gann, 75, 284-291; March, 1984] [Gann, 75, 284-291; March, 1984] EFFECTS OF ANTIPLATELET AGENTS ON PULMONARY METASTASES Hiroyasu BANDO,Takashi YAMASHITAand Eiro TSUBURA ThirdDepartment of InternalMedicine, The Universityof Tokushima,School of Medicine, Kuramoto-cho3-chome,T okushima770 The role of platelets in cancer metastasis was studied by investigating the effects of the antiplatelet agents ticlopidine, diltiazem, dipyridamole and trapidil on arti ficialand spontaneous pulmonary metastases in mice. These agents were tested at their optimal inhibitory doses on adenosine diphosphate-induced platelet aggrega tion;namely, 100mg/kg for ticlopidine, 2mg/kg for diltiazem, 180mg/kg for trapidil and 60mg/kg for dipyridamole. At these doses, trapidil caused moderate inhibition of thrombin-induced platelet aggregation in mice, but the other agents had only slight effects. Artificial pulmonary metastasis was produced by inoculation of Lewis lung carcinoma (LLC) or B16 melanoma (B16) cells into C57BL/6 mice . For induction of spontaneous pulmonary metastases, these tumor cells were implanted subcutane ouslyinto the footpads of mice. The resulting primary tumors of LLC and B16 were removed 9-10 and 17 days later, respectively. Artificial pulmonary metastases were inhibited significantly by all the antiplatelet agents tested . Spontaneous pulmonary metastases were markedly reduced only when these agents were given after removal of the primary tumor. The role of platelets is discussed with respect to thrombus formation in the lodgement of tumor cells and the participation of platelet -derived growth factor in the growth of metastatic foci. Key words: Blood-borne metastasis-Antiplatelet agents-B16 melanoma - Lewis lung carcinoma-Adenosine diphosphate-induced platelet aggregation The outcome of hematogenous metastasis To clarify the role of platelets in cancer depends on the interaction of tumor cells metastasis, we studied the effects of various with various host factors in the metastatic antiplatelet agents (platelet aggregation in process. The blood coagulation-fibrinolysis hibitors)with different modes of action (i .e., system is an important host factor , in which ticlopidine, diltiazem, dipyridamole and platelets are essential for blood coagulation. trapidil) on artificial and spontaneous pul Our previous studies on the inhibition of monarymetastases in mice . blood-borne metastases by sulfated poly saccharides23) and the defibrinogenating MATERIALS AND METHODS agent ancrod10) showed that intravascular Animals Male C57BL/6 mice aged 6-8 weeks, coagulation in the target organ is an impor weighing 20-25g, were purchased from Shizuoka tantmechanism at an early stage of hemato Animal Farm Co. (Shizuoka). genousmetastasis. Tumors LLC* and B16, which both arose spontaneously in C57BL/6 mice, have been main Abbreviations used: LLC , Lewis lung carcinoma;PD tainedby serial biweekly subcutaneous passage in GF, platelet-derived growth factor; B16 , B16 the same strain of mice. Tumor fragments were melanoma; ADP, adenosine diphosphate; PRP , stirred in RPMI 1640 medium (Microbiological platelet-rich plasma; PPP, platelet-poor plasma; Associates, Md.) containing 0.2% trypsin (1:250, CPA, cyclophosphamide. Difco Lab., Detroit, Mich.) at 37•‹ for 30 min 284 Gann METASTASIS AND ANTIPLATELET AGENTS (LLC) or 5min (B16). For intravenous inocula (B16) after tumor inoculation, and the lungs were tion,LLC tumor was treated with a solution of fixed in 10% formalin solution. Then the number DNase, collagenase I and anti-trypsin II-S (all of metastatic foci on the pulmonary surface was counted. purchased from Sigma Chemical Co., St. Louis) at 37•‹ for 45min. The isolated tumor cells were b) Spontaneous pulmonary metastasis: LLC washed twice with RPMI 1640 medium contain cells (1•~106/0.05ml) and B16 cells (5•~105/0.05 ing10% fetal calf serum (FCS, Gibco, Grand ml) were inoculated into the footpads of C57BL/6 Island, New York), resuspended and counted in mice. The tumor-bearing foot was amputated on a hemocytometer. B16 and LLC cells have been day 9 or 17 after tumor inoculation. The effects demonstrated to have strong and moderate ac of antiplatelet agents on different metastatic pro tivities,respectively, for aggregation of platelets.22) cesseswere examined, in mice bearing LLC, by Antiplatelet Agents Ticlopidine (Daiichi Phar giving antiplatelet agents from day 5 to day 9 or maceuticalCo., Tokyo), diltiazem (Tanabe Phar from day 9 to day 14, and in mice bearing B16, maceuticalCo., Tokyo), dipyridamole (Japan by giving antiplatelet agents from day 9 to day Boehringer Ingelheim Co., Tokyo) and trapidil 17 or from day 17 to day 23. c) Combined effect of antiplatelet agents and (Mochida Pharmaceutical Co., Tokyo) were used as antiplatelet agents. These drugs were diluted anticancer agents: Inocula of 1•~106 LLC cells with water to the desired concentration and ad were implanted into the footpad and the primary ministeredorally by stomach tube to mice in a tumor was removed 10 days later. Antiplatelet volume of 0.2ml. Ticlopidine and diltiazem were agents were given for 6 days after removal of the administered daily, whereas dipyridamole and tumor. A single dose of 50 mg/kg of CPA was in trapidil were administered twice a day. jectedip on the day after removal of the implanted Ticlopidine, first described by Podesta et al.,20) tumor. is thought to enhance adenylate cyclase activity.) Mice were sacrificed on day 21 (LLC) or day Diltiazern is a Ca antagonist enhancing adenylate 36 (B16) after tumor inoculation. Antimetastatic cyclase activity.21) Dipyridamole is an inhibitor activity was measured as described above. of cyclic-AMP phosphodiesterase, increasing pro ductionof prostacyclin.18) Trapidil mainly inhibits RESULTS thromboxane synthetase activity and has the same action as anti PDGF.19) Inhibitory Effect of Antiplatelet Agents Platelet Aggregating Agents ADP (Sigma on ADP-induced Platelet Aggregation Chemical Co.) and thrombin (Miles Labo., In Fig. 1 shows the inhibitory effect of anti diana)were used. PRP PRP was obtained from citrated blood of plateletagents on ADP (400ƒÊM in 10mM mice. The number of platelets was adjusted to CaCl2)-induced PRP aggregation. Ticlopi approximately 2•~105/ƒÊl by adding PPP or saline. dineinhibited the aggregation of platelets PRP for platelet aggregation tests was prepared at a clinical dose of 12mg/kg, and had the 3hr after oral administration of ticlopidine or same inhibitory effect at doses of 60mg/kg, diltiazem, and 1hr after administration of dipy ridamoleor trapidil. PRP from mice treated with 120mg/kg and 360mg/kg. Diltiazem caused each agent for 2 days was also prepared 2, 5, 9 and only weak inhibition of platelet aggregation 12 days after the beginning of drug administration at any dose. Dipyridamale and trapidil in and the platelet activities were examined. hibitedaggregation only weakly at doses of Platelet Aggregation Platelet aggregation was measured turbidometrically with an Autoram-31 2mg/kg and 6mg/kg, respectively, but caused type aggregometer (Rika Denki Co., Tokyo). marked inhibition at doses of 60mg/kg and Platelet aggregation was tested by adding 30ƒÊl 180mg/kg, respectively. Based on these re of a solution of aggregating agent, such as ADP sults,we used doses of 100mg/kg (ticlopidine), (400ƒÊM or 20ƒÊM in 10mM CaCl2) or thrombin 2mg/kg (diltiazem), 60mg/kg (dipyridamole) (20 NIH units/ml) to 0.27ml of PRP. Assay of Pulmonary Metastases and 180mg/kg (trapidil) for experiments a) Artificial pulmonary metastasis: LLC cells on metastases. (1•~106 in 0.2ml of RPMI 1640) or B16 cells (3•~ Inhibitory Effects of Antiplatelet Agents 105 in 0.2ml of RPMI 1640) were inoculated into on Thrombin-induced Platelet Aggrega C57BL/6 mice via the tail vein. Agents were given to mice orally for 2 days before tumor inoculation. tionAs shown in Fig. 2, trapidil (180mg/ The mice were killed 9 days (LLC) or 20 days kg) inhibited thrombin (20 NIH units/ml)- 75(3) 1984 285 H. BANDO, ET AL. Fig. 1. Inhibition of ADP-induced platelet aggregation by antiplatelet agents Control (• ). Ticlopidine (•› 12, •¢ 60, •£ 120, •¡ 360mg/kg), diltiazem (•› 2, •¢ 20, •£ 60mg/kg), dipyri damole(•› 2, •¢ 10, •£ 20, •¡ 60mg/kg) and trapidil (•› 6, •¢ 30, •£ 60, •¡ 180mg/kg) were given orally to mice. induced PRP aggregation moderately, while Effects of Antiplatelet Agents on Arti ticlopidine (100mg/kg), diltiazem (2mg/kg) ficialPulmonary Metastases All anti and dipyridamole (60mg/kg) inhibited this plateletagents tested inhibited the develop aggregation only slightly. mentof artificial pulmonary metastases of Change in Platelet Function in Mice both LLC and B16. Metastases of LLC were Treated with Antiplatelet Agents Next inhibited markedly in mice treated with we studied the time course of change in diltiazem or dipyriamole, while metastases platelet aggregation after treatment with of B16 were significantly inhibited by ticlo antiplatelet agents (Fig. 3). The platelet- pidine,diltiazem and trapidil (Table I). aggregating activity decreased on the day Effects of Antiplatelet Agents on Spon after treatment, but returned to normal 3 taneousPulmonary Metastases As days after treatment. No rebound phenome shown in Table II, no significant inhibitory nonor delayed inhibitory effect on platelet effects on spontaneous pulmonary metastases aggregation was observed. were observed in mice treated with anti- 286 Gann METASTASIS AND ANTIPLATELET AGENTS Fig. 2. Inhibitory effects of antiplatelet agents on thrombin-induced platelet aggregation Control (• ). Ticlopidine (•£ 100mg/kg),
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