phosphomannopentaose-sulfate and Neoplasm-Metastasis

The heparan sulfate (HS) mimetic PI-88 is a promising inhibitor of tumor growth and metastasis expected to commence phase III clinical evaluation in 2007 as an adjuvant therapy for postresection hepatocellular carcinoma. Its anticancer properties are attributed to inhibition of angiogenesis via antagonism of the interactions of angiogenic growth factors and their receptors with HS. It is also a potent inhibitor of heparanase, an enzyme that plays a key role in both metastasis and angiogenesis. A series of PI-88 analogs have been prepared with enhanced chemical and biological properties. The new compounds consist of single, defined oligosaccharides with specific modifications designed to improve their pharmacokinetic properties. These analogs all inhibit heparanase and bind to the angiogenic fibroblast growth factor 1 (FGF-1), FGF-2, and vascular endothelial growth factor with similar affinity to PI-88. However, compared with PI-88, some of the newly designed compounds are more potent inhibitors of growth factor-induced endothelial cell proliferation and of endothelial tube formation on Matrigel. Representative compounds were also tested for antiangiogenic activity in vivo and were found to reduce significantly blood vessel formation. Moreover, the pharmacokinetic profile of several analogs was also improved, as evidenced primarily by lower clearance in comparison with PI-88. The current data support the development of HS mimetics as potent antiangiogenic anticancer agents.

Topics: Animals; Biomimetic Materials; Carcinoma, Hepatocellular; Cell Proliferation; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Endothelial Cells; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Heparin Lyase; Heparitin Sulfate; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Oligosaccharides; Vascular Endothelial Growth Factor A

Topics: Animals; Cell Proliferation; Gene Expression Regulation, Enzymologic; Glucuronidase; Humans; Myocytes, Smooth Muscle; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oligosaccharides

Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.. We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m(2) dose every three weeks. Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6-99 weeks) and 1-year survival was 71%.. The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Dose-Response Relationship, Drug; Glucuronidase; Humans; Male; Middle Aged; Neoplasm Metastasis; Oligosaccharides; Prostatic Neoplasms; Taxoids; Treatment Failure

Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >or=20%, there is some evidence of activity and further investigation is warranted.

Topics: Adult; Aged; Alanine Transaminase; Contusions; Drug Administration Schedule; Fatigue; Female; Glucuronidase; Humans; Injections, Subcutaneous; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Nausea; Neoplasm Metastasis; Oligosaccharides; Pain; Severity of Illness Index; Thrombocytopenia; Treatment Outcome

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.

Topics: Animals; Antineoplastic Agents; Carbohydrate Sequence; Drug Screening Assays, Antitumor; Female; Glucuronidase; Glycoside Hydrolases; Humans; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Neoplasm Metastasis; Neoplasm Proteins; Neovascularization, Pathologic; Oligosaccharides; Organ Culture Techniques; Placenta; Rats; Rats, Inbred F344; Sulfur