SURAMIN IN LYMPHOMA--CLINICAL AND MECHANISTIC STUDIES

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Suramin is a polysulfonated nephthylurea with significant clinical activity against metastatic hormone refractory cancer of the prostate and low grade lymphoma. However, the toxicity observed in these early trials was substantial. Although suramin binds to many proteins of biological interest, its anti-tumor mechanism of action remains obscure. In addition, very little is understood about the cellular pharmacology of suramin: Such knowledge is vital in order to develop more clinically effective suramin analogs. We propose a Phase II trial of suramin in chemotherapy refractory low grade lymphoma. All patients will undergo treatment with suramin by the NCI fixed intermittent bolus schedule. Patients will have a tumor deposit biopsied, and the malignant lymphocytes obtained will be grown in short term culture for the studies given below. The response rate to suramin, with sufficient statistical power, will be determined. We hypothesize that parameters such as 1) kinetic and equilibrium parameters of cell surface binding; 2) rates and mechanisms of internalization; 3) patterns of intracellular distribution; 4) rates and mechanisms of efflux; 5) accessibility of the putative intracellular target mechanisms to suramin will affect the response rates. We will obtain fluorescently-labeled suramin analogs, and will monitor the rates of endocytosis and exocytosis, both in tumor biopsy specimens and lymphoid cell lines using flow cytometry. We will determine if fluorescein-suramin enters an acidic environment by treatment of cell with the ionophore monensin, and with the macrolide antibiotic bafilomycin, which specifically blocks the function of the H+- vacuolar ATPase. We will calculate the kinetic constants A, alpha, B Beta, etc. The average intracellular pH of the suramin-containing compartment will be calculated. The approximate concentration of suramin available to the cytoplasmic compartment will be determined, and the concentration in this compartment increased by osmotic lysis of the endosome. We will correlate these data, when obtained from biopsy specimens, with the observed clinical responses. As part of the effort to improve the therapeutic efficacy of suramin, we will obtain and evaluate suramin analogs from Dr. D., Rideout. These will be evaluated in selected systems in which suramin has activity,. These systems are 1) Inhibition of growth of biopsy derived malignant lymphocytes and lymphoma cell lines; 2) Binding of heparin-binding growth factors (bFGF, PDGF) to their cell surface receptors; 3) Binding of LDL and transferrin in their cell surface receptors; 4) Inhibition of PKC-Beta1 phosphorylating ability; and 5) Inhibition of the activity of the glycosaminoglycan catabolizing enzymes L-iduronate sulfatase and Beta- glucuronidase. These data will help define the mechanism of action of suramin, as well as provide leads for further drug development.