1-5-dihydro-7-(1-piperidinyl)-imidazo(2-1-b)quinazolin-2(3h)-one and Lung-Neoplasms

DN-9693, c-AMP: phosphodiesterase inhibits platelet aggregation induced by metastasizing tumor cells and blood-borne metastases of these tumors. Effects of this drug on pulmonary metastases was studied in wKA rats, which were sc implanted with 4-dimethylaminoazobenzene (DAB) induced KDH-8 tumor cells. KDH-8 cells (10(5)) were sc inoculated on day 0 and excised on day 20. DN-9693 was ip injected at a dose of 150 micrograms twice a day for 7 days pre operatively (-7 - 0) or perioperatively (-3 - +3) or postoperatively (0 - +7). The rats were sacrificed on day 20 after surgery, and lung weight and the number of surface pulmonary nodules were measured. Both were significantly decreased in the group of perioperative and postoperative administration of DN-9693. The survival of these rats were furthermore prolonged when Cyclophosphamide (40 mg/kg) was sc injected 3 days after surgical resection. KDH-8 tumor cells (10(4)) were iv inoculated on day 0, and DN-9693 was ip injected at a dose of 150 micrograms twice a day for 7 days on day 0 approximately 7. Rats were sacrificed on day 20, and same studies as above were done. In this artificial pulmonary metastases, the decrease of the number of lung nodules was observed in WKA rat treated with DN-9693. Platelet aggregation induced by KDH-8 tumor cells was inhibited by ADP inhibitor (apyrase, CP/CPK) and thrombin inhibitor (heparin, MD-805); KDH-8 tumor cells induced platelet aggregation by two different mechanisms: ADP-mediated aggregation and thrombin-mediated aggregation. This platelet aggregation by KDH-8 tumor cells was inhibited by DN-9693 with dose-dependency. DN-9693 had no direct anti-tumor effects either in vivo or in vitro. The results indicates that this drug prevents pulmonary metastases by inhibiting platelet aggregation.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Lung Neoplasms; Neoplasm Metastasis; Neoplasm Transplantation; Platelet Aggregation Inhibitors; Quinazolines; Rats; Rats, Inbred Strains

The effects of DN-9693, a platelet aggregation inhibitor, on tumor cell attachment to endothelium were investigated to clarify its inhibitory action on metastasis. The role of platelets in the attachment of murine metastasizing tumor cells to endothelium was first examined in vitro. Morphological studies and quantitative isotope measurements revealed that tumor-cell-activated platelets significantly enhanced tumor cell attachment to the endothelium. This amplification is considered to depend on morphological and functional changes of endothelial cells: activated platelets may accelerate endothelial retraction, exposing more reactive subendothelium, and may increase the adhesiveness of endothelial cells. The platelet-enhanced tumor cell attachment to the endothelium was inhibited in the presence of DN-9693. The pretreatment of endothelial cells with the compound was also effective in inhibiting cell attachment. These data suggest that the inhibitory effects of DN-9693 on metastasis are in part mediated by the prevention of tumor cell attachment to the vascular endothelium.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Blood Platelets; Calcium; Cells, Cultured; Endothelium, Vascular; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Neoplasms, Experimental; Platelet Activation; Platelet Aggregation Inhibitors; Pulmonary Artery; Quinazolines; Tumor Cells, Cultured