DETECTABLE INHIBITION OF HEPARIN-BINDING GROWTH-FACTOR ACTIVITY IN SERA FROM PATIENTS TREATED WITH PENTOSAN POLYSULFATE

Background: Previous studies indicate that the heparinoid pentosan polysulfate (PPS) can inhibit heparin-binding growth factors (HBGFs) released from tumor cells and thus block tumor growth in animal models. However, because of its heparin-like activity, the major toxic effect expected for PPS is its inhibition of coagulation. Purpose: Our purpose was to determine if anti-HBGF activity could be achieved in patients without causing complications from anticoagulation. Methods: We initiated a phase I trial in cancer patients and developed a cell proliferation assay to detect PPS in human serum based on its anti-growth factor activity. Blood samples from six healthy volunteers were collected in tubes containing different concentrations of PPS (FIBREZYM; concentration range, 0-10 mug/mL). Additional samples were obtained from four patients in the phase I trial before and after subcutaneous treatment with 15 mg/m2 of PPS. The activated partial thromboplastin time (aPTT), which is associated with coagulation, was measured in all blood samples. Serum prepared from the blood samples was heat inactivated and then incubated for 4-5 days with proliferating SW-13 cells, allowing determination of antigrowth factor activity. Results: PPS added to blood samples increased aPTT only at concentrations above 1 mug/mL, whereas HBGF-dependent proliferation was inhibited at less than 0.1 mug/mL. Sera obtained from patients up to 4 hours after PPS treatment specifically inhibited HBGF-dependent cell proliferation by more than 65% even at a 1:10 dilution. At the same time, the aPTT was not altered in these patients, indicating no significant effect on coagulation by this dose of the heparinoid. Conclusions: HBGF-inhibitory concentrations of PPS can be achieved in patients' sera without significant effects on coagulation. Implication: The assay presented here could be useful to determine doses and scheduling of treatment in studies evaluating PPS as an antitumor agent.