Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity.
Inhibitors of tumor angiogenesis and metastasis are rapidly emerging as important new drug candidates for cancer therapy. To facilitate the identification of such drugs, we recently developed novel and rapid in vitro assays for human angiogenesis and for the extracellular matrix-degrading enzyme heparanase, which has been implicated in tumor metastasis. In this study, sulfated oligosaccharides, which are structural mimics of heparan sulfate, were investigated as drug candidates because these compounds may interfere with heparan sulfate recognition by many angiogenic growth factors and may inhibit cleavage of heparan sulfate by heparanase. In the preliminary screening studies, it was found that inhibitory activity in both assay systems was critically dependent on chain length and degree of sulfation, highly sulfated linear oligosaccharides of five or more monosaccharides in length being the most active. However, two sulfated oligosaccharides stood out as potential antitumor drugs, phosphomannopentaose sulfate (PI-88) and maltohexaose sulfate, both of these compounds having the important property of simultaneously being potent inhibitors of in vitro angiogenesis and heparanase activity. Due to the ease of manufacture of the starting material, phosphomannopentaose, PI-88 was studied in more detail. PI-88 was shown to inhibit the primary tumor growth of the highly invasive rat mammary adenocarcinoma 13762 MAT by approximately 50%, inhibit metastasis to the draining popliteal lymph node by approximately 40%, and reduce the vascularity of tumors by approximately 30%, all of these effects being highly significant. Acute hematogenous metastasis assays also demonstrated that PI-88 was a potent (>90%) inhibitor of blood-borne metastasis. Thus, by the use of novel in vitro screening procedures, we have identified a promising antitumor agent.
Parish
C R
CR
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra. Christopher.Parish@anu.edu.au
Freeman
C
C
Brown
K J
KJ
Francis
D J
DJ
Cowden
W B
WB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002240:Carbohydrate Sequence; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000032:analysis*; D006801:Humans; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000032:analysis*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D010920:Placenta / Q000098:blood supply; D051381:Rats; D011916:Rats, Inbred F344; D013455:Sulfur; D000099175:Heparanase
D000970:Antineoplastic Agents; D005966:Glucuronidase; D006026:Glycoside Hydrolases; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D013455:Sulfur; D000099175:Heparanase; C120498:maltohexaose sulfate; C120158:phosphomannopentaose sulfate