ADMINISTRATION OF PENTOSAN POLYSULFATE TO PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED KAPOSI-SARCOMA

Background: Neovascularization induced by basic fibroblast growth fact or (basic FGF) or FGF-like cytokines is thought to play a substantial role in the pathogenesis of human immunodeficiency virus (HIV)-associa ted Kaposi's sarcoma. Pentosan polysulfate has been shown to inhibit b asic FGF and FGF-like dependent tumor growth both in vitro and in vivo . Moreover, it has been found to inhibit the growth of Kaposi's sarcom a-derived spindle cells in vitro. These observations suggested that pe ntosan polysulfate might be worth exploring as a potential agent for t he treatment of Kaposi's sarcoma. Purpose: The purpose of this phase I clinical trial was to determine the maximum tolerated dose of pentosa n polysulfate in patients with HIV-associated Kaposi's sarcoma and whe ther or not this compound had activity against this neoplasm. Methods: Sixteen HIV-seropositive patients with Kaposi's sarcoma received pent osan polysulfate via continuous venous infusion for 3-6 weeks and then received a subcutaneous dose three times per week. Three different do ses of pentosan polysulfate were administered: 2 mg/kg per day by infu sion followed by 2 mg/kg per dose given subcutaneously (six patients), 3 mg/kg per day by infusion followed by 3 mg/kg per dose given subcut aneously (five patients), and 4 mg/kg per day by infusion followed by 4 mg/kg per dose given subcutaneously (five patients). Five of the 16 patients in the study also received injections of 1 mg of pentosan pol ysulfate into two different lesions two times a week for 3 weeks, foll owed by intralesional therapy once weekly. After receiving pentosan po lysulfate for 6 weeks, patients were administered 100 mg zidovudine (A ZT) orally every 4 hours in conjunction with pentosan polysulfate. Res ults: The maximally tolerated dose of pentosan polysulfate given by co ntinuous venous infusion was found to be 3 mg/kg per day. No patient h ad an objective clinical antitumor response to either systemic or intr alesional pentosan polysulfate administration; however, three patients had stable Kaposi's sarcoma for 3-27 weeks. No statistically signific ant effect on CD4 cells or serum HIV p24 antigen was noted during pent osan polysulfate administration. Dose-limiting toxic effects were char acterized by anticoagulation and thrombocytopenia and were reversible. Conclusion: Pentosan polysulfate was well tolerated in this patient p opulation. However, no objective tumor response or evidence of anti-HI V activity was noted; therefore, no claim of activity can be made in t his trial. Implication: Continued investigation into the use of angiog enesis inhibitors with improved activity and toxicity profiles or diff erent mechanisms of action is warranted.