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Detectable inhibition of heparin-binding growth factor activity in sera from patients treated with pentosan
B W Parker1, S M Swain, G Zugmaier
1V.T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D.C. 20007.
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 antigrowth factor activity. Blood samples from six healthy volunteers were collected in tubes containing different concentrations of PPS (FIBREZYM; concentration range, 0-10 micrograms/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 microgram/mL, whereas HBGF-dependent proliferation was inhibited at less than 0.1 microgram/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.