cgp-48664 and Adenocarcinoma

Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines including spermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancer samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P < 0.0001), tumor size (P < 0.0001), tumor differentiation (P < 0.05), tumor venous invasion (P < 0.0001), tumor lymphatic invasion (P < 0.0001), blood vessel invasion (P < 0.0001), and tumor lymph node metastasis (TNM) stage (P < 0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Adult; Aged; Aged, 80 and over; Amidines; Animals; Carcinogenesis; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; G1 Phase Cell Cycle Checkpoints; Gene Knockdown Techniques; Helicobacter Infections; Helicobacter pylori; Humans; Indans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Polyamines; Prognosis; Stomach; Stomach Neoplasms; Xenograft Model Antitumor Assays

CGP 48664A (2-(4-aminoiminomethyl)-2,3-dihydro-1H-inden-1-ylidene dihydrochloride, CAS 149400-88-4) is a new potent inhibitor of S-adenosylmethionine decarboxylase with antitumor properties. In view of the eminent clinical problems in the treatment of non hormone dependent prostatic cancer, the antiproliferative potency of this compound was tested in Dunning MAT-LyLu rat prostatic adenocarcinoma. The compound proved inefficient in preventing the growth of this tumor, even at a near toxic dose. A reason for the lacking effect is presumably the inadequate accumulation of the drug in the tumor cells due to the excessive growth rate of the MAT-LyLu xenografts. Tumor growth seems not to be accompanied by a proportionally rapid vascularization of the tumor mass. CGP 48664A was found to be a potent inhibitor of polyamine oxidase. This property of the drug may have contributed to the activation of the phagocytic capacity of peritoneal macrophages from tumor-bearing rats.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Amidines; Animals; Antineoplastic Agents; Biogenic Polyamines; Body Weight; Enzyme Inhibitors; Indans; Liver; Lung Neoplasms; Macrophages, Peritoneal; Male; Neoplasm Transplantation; Organ Size; Phagocytosis; Prostatic Neoplasms; Rats; Rats, Inbred Strains