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

Background: Previous studies indicate that the heparinoid pentosan pol ysulfate (PPS) can inhibit heparin-binding growth factors (HBGFs) rele ased from tumor cells and thus block tumor growth in animal models. Ho wever, because of its heparin-like activity, the major toxic effect ex pected for PPS is its inhibition of coagulation. Purpose: Our purpose was to determine if anti-HBGF activity could be achieved in patients w ithout causing complications from anticoagulation. Methods: We initiat ed a phase I trial in cancer patients and developed a cell proliferati on 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; concentrat ion range, 0-10 mug/mL). Additional samples were obtained from four pa tients in the phase I trial before and after subcutaneous treatment wi th 15 mg/m2 of PPS. The activated partial thromboplastin time (aPTT), which is associated with coagulation, was measured in all blood sample s. Serum prepared from the blood samples was heat inactivated and then incubated for 4-5 days with proliferating SW-13 cells, allowing deter mination of antigrowth factor activity. Results: PPS added to blood sa mples increased aPTT only at concentrations above 1 mug/mL, whereas HB GF-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 p atients, 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 coagu lation. Implication: The assay presented here could be useful to deter mine doses and scheduling of treatment in studies evaluating PPS as an antitumor agent.