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Suramin: here to stay!?

Suramin was one of the first chemotherapeutic agents developed with efficacy against a parasitic disease. Originally synthesized in the early 1900s, the drug was extensively used in the 1920s and 1930s. Clinical use waned until in vitro studies showed that suramin could inhibit reverse transcriptase and antagonize the binding of a number of polypeptide growth factor ligands (platelet-derived growth factor, basic fibroblast growth factor, transforming growth factor-p, and epidermal growth factor) with their receptors. Demonstration of antitumor activity in hormone-refractory prostatic cancer, a disease for which there is no effective therapy, generated even more interest in the compound. The highly charged nature of suramin results in a significant degree of protein binding, a factor that may contribute to its diverse biologic actions. Suramin not only affects interactions between growth factor and growth factor receptors—it can also induce differentiation (7) and inhibit mitochondrial function (2), adrenal steroidogenesis (3), protein kinase C (4), glycolysis (5), membrane-associated ion pumps (6), and the metastatic process through an effect on cell motility (7). The effects are nonspecific, and currently, it is unclear whether the tumoricidal action is the result of the extracellular or the intracellular effects of the compound. Suramin was evaluated in prostatic cancer on the basis of the inhibitory effects on growth-factor-induced mitogenesis and proliferation and antitumor activity against humanderived prostatic cancer cell lines in vitro and in vivo (8). The initial report by Myers et al. (8) in 1989 showed measurable disease response in four of eight patients and prostate-specific antigen (PSA) declines in seven of 11 patients treated. In that trial, suramin was administered by continuous infusion until a target concentration of 280-300 Hg/mL was reached. Due to the effects on the adrenal gland, all patients received hydrocortisone replacement from the start of treatment. While the reported therapeutic efficacy stimulated intense interest, the drug also achieved notoriety for its seemingly prohibitive toxic effects profile. The situation was not dissimilar to that observed with the earliest use of cisplatin. Some toxic effects, such as the skin rash, are idiosyncratic (9), while others, such as the vortex keratopathy and coagulopathy, are related to the inhibitory effects of suramin on glycosaminoglycan synthesis (10,11). Other side effects include renal insufficiency, adrenal insufficiency, thrombocytopenia, hepatitis, and an increased incidence of infection despite normal blood counts. The most feared complication is peripheral neuropathy, which can progress to a Guillain-Barre' syndrome (72). Based on early National Cancer Institute (NCI) results, confirmatory trials at Memorial Sloan-Kettering Cancer Center, M. D. Anderson Cancer Center, and the Mayo Clinic were initiated. Proportionally, fewer patients responded to the drug. The results, using a variety of dosing regimens, are summarized in Table 1. Why, then, were investigators so persistent? First, those of us who treat prostatic cancer recognize the importance of not discarding a drug with potential activity. Second, despite fewer responses in some series, some of the responses lasted for more than 1 year, a phenomenon rarely observed in hormone-refractory disease. Third, other investigations were observing responses with different schedules (Table 1). These developments generated an intensive series of investigations to improve the therapeutic index of the compound. In vitro, the antitumor effect of suramin is dependent on both the concentration of the drug and the time of exposure. Further, a pharmacokinetics evaluation (75) of the first six patients treated at Memorial Sloan-Kettering Cancer Center revealed significant interpatient variability. These observations, coupled with the postulated therapeutic window (see below), led to the design of schedules in collaboration with the University of Maryland that maintain plasma concentrations in a defined range for prolonged durations. In this issue of the Journal, Eisenberger et al. (14) present the first report of the University of Maryland experience. The study by Eisenberger et al. (14) represents an enormous effort by a closely integrated team of medical oncologists, pharmacologists, pharmacokineticists, research nurses, technicians, and data managers. Here is their treatment schema: A population-based pharmacokinetics profile is derived first. A new patient is then treated, and plasma concentrations are determined both before and after each drug treatment. With the use of a high-speed computer, these concentrations are combined with the population-based model to estimate the pharmacokinetics for the patient. A dosing recommendation is then given. The process is repeated on each day of therapy. As more plasma concentrations are determined, the pharmacokinetic estimates are updated. After the five daily treatments in week 1, steady state is approached, the time to decline to the desired trough level is estimated, and the patient is asked to return on that particular day. Thus, the schedule is flexible both with respect to the amount of drug administered and to the timing of the administration. This process is extremely labor intensive for both the patient and the treating team. Their efforts appear to be justified, though, because the results in prostatic cancer showed measurable disease regression in six of 12 patients (50%; 95% confidence interval = 22%-78%); 24 of 31 patients (77%; 95% confidence interval = 63%-92%) had a greater than 50% decline in PSA from