Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specifi c biological phenotypes and increase the anti-tumor effect when combined wi th chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a he parin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibit or, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeuti c agent were selected. The effects of each drug on colony formation and tum or cell proliferation were evaluated by soft agar assay and cell proliferat ion assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by z ymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Mi gration capacity using Boyden chamber assay was more closely correlated wit h adhesive capacity than uPA or MMP-2 expression. The motility inhibitory e ffect of Tranexamic acid was observed in the YCC-7 cell line, which express ed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin an d most of the inhibitory effect was recovered by Mevalonate. When PPS was c ombined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expr essing YCC-7 cell line, the growth inhibition rate increased up to 84%, whi le that for a single treatment of PPS or Adriamycin was 40% and 22%, respec tively (p = 0.001). When we combined Tranexamic acid and Adriamycin, we obs erved the synergistic effect in YCC-3 and YCC-7, while no combined effect w as found in YCC-1. The combination of Lovastatin and Adriamycin did not sho w any combined effects in any of the cell lines. In conclusion, a synergist ic anti-proliferative effect (chemo-sensitization) with combined chemo-biot herapy was found in cancer cells with specific biological target, MK. The a nti-motility effect was the greatest when the gastric cancer cells expresse d all the specific biological phenotypes.