Kiyoshi Morikawa

Clonal stimulation or inhibition of human colon carcinomas and human renal carcinomas mediated by transforming growth factor-beta 1.

We examined various human carcinomas and cells populating a single human neoplasm to determine whether they exhibit a heterogeneous response to the effects of transforming growth factor-beta 1 (TGF-beta). Using recently established human colon carcinoma and renal cell carcinoma under defined in vitro conditions, we observed intertumoral and intratumoral heterogeneity and polarity of responses to TGF-beta (growth inhibition or stimulation) that did not correlate with the metastatic phenotype of the cancer cells as assessed in athymic nude mice. TGF-beta mediated both cytostatic and cytolytic effects against sensitive tumor cells, and these responses were not related to the effects of TGF-beta on the cell-cycle traverse. The human colon carcinoma and renal cell carcinoma, however, exhibited differences in the expression of TGF-beta receptors.

A NEW ANTI-METASTATIC DRUG, ND-2001, INHIBITS LUNG METASTASES IN RAT HEPATOMA CELLS BY SUPPRESSING HAPTOTAXIS OF TUMOR CELLS TOWARD LAMININ

We examined the effects of ex vivo treatment of tumor cells with sodium D-glucaro-δ-lactam (sodium 5-amino-5-deoxy-D-glucosaccharic acid-δ-lactam; ND-2001). The ex vivo treatment of rat hepatoma cKDH-8/11 cells with this new synthetic product of the antibiotic nojirimycin, ND-2001 (50 μg/ml), inhibited the experimentally induced lung metastases of the tumor cells significantly at an inhibition rate of 69.2% (one of 10 animals remained metastasis free). Also, it was elucidated in in vivo tumor cell invasion assays that ND-2001 (50 μg/ml) suppressed the invasion activities of cKDH-8/11 cells to Matrigel™ Matrix at an inhibition rate of 69.3%. However, phagokinetic track assays revealed that ND-2001 did not suppress the random motility of cKDH-8/11 cells. However, ND-2001 (50 μg/ml) suppressed the haptotaxis, another important role in tumor invasion, of cKDH-8/11 cells toward laminin (inhibition rate of 77.0%). These results suggest that ND-2001 suppressed the haptotaxis of tumor cells toward laminin directly at the step of invading the basement membrane and brought about the inhibition of lung metastases.

ND-2001 suppresses lung metastasis of human renal cancer cells in athymic mice.

Explants of highly metastatic human renal cell carcinoma SN12Cpm6 cells in athymic mice were treated with sodium D-glucaro-delta-lactam (sodium 5-amino-5-deoxy-D-glucosaccharic acid-delta-lactam; ND-2001). ND-2001 (50 micrograms/ml) caused 78% inhibition of lung metastasis of SN12Cpm6 cells (two of five animals remaining metastasis free). The in vitro tumor cell invasion assay showed that ND-2001 (100 micrograms/ml) suppressed the invasive activity of SN12Cpm6 cells to Matrigel matrix at an inhibition rate of 72%. These results suggest that ND-2001 may be a new anti-metastatic drug against human cancer cells.