iloprost and Melanoma

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

The antimetastatic effect of the antithrombotic agents exogenous prostacyclin (PGI2) and a synthetic analog, Iloprost, on experimental metastasis formation was studied by injecting BL6 melanoma cells into C57BL/6 mice. Suitable in vivo treatment conditions were selected according to the known properties of the two drugs, including their pharmacokinetics. Iloprost showed a greater ability to inhibit platelet aggregation induced by BL6 melanoma cells. PGI2 displayed a limited antimetastatic activity, largely dependent on the tumor cell load and treatment schedule. Iloprost showed a far superior activity, its antimetastatic effect lasting longer and remaining detectable up to 6 h after tumor cell inoculation. The present data complex provides further support to the concept of a crucial role for platelet-tumor cell interaction in the process of metastasis formation.

Topics: Animals; Cell Line; Epoprostenol; Iloprost; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplastic Cells, Circulating; Platelet Aggregation