Inhibition of tumor cell-platelet interactions and tumor metastasis by the calcium channel blocker, nimodipine.
Nimodipine, a dihydropyridine calcium channel blocker, was evaluated in vitro for its ability to inhibit platelet aggregation induced by B16 amelanotic melanoma (B16a) and Walker 256 carcinosarcoma (W256) cells, and for its ability to inhibit platelet-enhanced B16a and W256 adhesion to rat microvascular endothelial cells. Nimodipine produced a dose-dependent inhibition of tumor-cell-induced platelet aggregation (TCIPA). Platelets enhanced tumor cell adhesion to endothelium both in the presence and absence of overt platelet aggregation. However, the greatest enhancement of adhesion occurred under aggregatory conditions. Nimodipine at a dose of 40 micrograms/ml inhibited platelet-enhanced adhesion to endothelium under aggregatory and nonaggregatory conditions. Nimodipine was tested in vivo for its ability to inhibit both "experimental' and spontaneous metastasis. Nimodipine produced a 46 per cent inhibition of lung colony formation at a dose of 5 mg/kg body-weight. Over a dose range of 0.1-80 mg/kg, nimodipine produced a significant dose-dependent inhibition in the formation of lung metastases from a subcutaneous tumor. The in vitro results demonstrate that a dihydropyridine calcium channel blocker can inhibit tumor cell-platelet-endothelial cell interactions. The in vivo results suggest that these compounds may be a new class of antimetastatic agent.
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D002279:Carcinoma 256, Walker / Q000188:drug therapy / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009539:Nicotinic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D009553:Nimodipine; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats
D002121:Calcium Channel Blockers; D009539:Nicotinic Acids; D009553:Nimodipine