gem-Diamine 1-N-Iminosugars and Related Iminosugars, Candidate of Therapeutic Agents for Tumor Metastasis

Yoshio      Nishimura

Abstract

Cancer metastasis is one of the major challenges in cancer research. Inhibitors of tumor metastasis are rapidly emerging as important new drug candidates for cancer therapy. Tumor metastasis formation occurs via a complex multistage process which involves a crucial step of tumor invasion through the basement membrane. Tumor cell invasion involves attachment of tumor cell to the basement membrane through laminin, degradation of the matrix by proteolytic enzymes from the tumor cell and cell migration through the basement membrane. New drugs aimed at the metabolism of tumor cell surface oligosaccharides and / or catabolism of glycoconjugates of extracellular matrix and basement membrane could inhibit tumor metastasis. In this article, current progress in the control of tumor metastasis by gem-diamine 1-N-iminosugars and related iminosugars (nojirimycin and D-glucaro-δ-lactam), which are potent and specific inhibitors of carbohydrate metabolism and catabolism, has been reviewed. gem-Diamine 1-N-iminosugars related to D-glucuronic acid and L-iduronic acid, nojirimycin and D-glucaro-δ-lactam suppress invasion of B16 melanoma variants and 3LL (lung carcinoma) cells through reconstituted basement membrane, and inhibit pulmonary metastasis of these tumor cells in mice and / or cKDH-8 / 11 (liver carcinoma) cells in rats. These results suggest that the metabolism of β-D-glucuronide and α-L-iduronide of glycoconjugates and / or the processing of carbohydrates of tumor cell surface may participate in tumor metastasis. That these gem-diamine 1-N-iminosugars and related iminosugars are potent inhibitors of tumor metastasis holds promise of new drug candidates for cancer chemotherapy.

Keywords: metastasis, Invasion, glucuronidase, gem-diamine 1-n-iminosugar, nojirimycin, nd2001, d-glucuronic acid, l-iduronic acid