Suramin: a Novel Antineoplastic Agent with Multiple Potential Mechanisms of Action1

[CANCER RESEARCH 53. 2239-2248. May 15. 1993]

Perspectives in Cancer Research

Suramin: A Novel Antineoplastic Agent with Multiple Potential Mechanisms of Action1

C. A. Stein n?partmenl of Medicine. Columbia University. College of Physicians and Surgeons. New York. New York

In the June 1992 edition of the Journal of Clinical Oncology, Myers Hawking (6). He noted that the drug could bind to and inhibit the el al. ( 1) reported on 38 cases of metastatic hormone refractory pros function of a wide variety of enzymes and proteins, although he could tate cancer treated with suramin, a bis-polysulfonated naphthylurea. In detect no underlying unifying themes. These enzymes included hy- the accompanying editorial. Pinedo and van Rijswijk (2) state that aluronidase, fumarase, urease, hexokinase, Na+-K^ ATPase and RNA "there can be little doubt that suramin represents an important new polymerase. Suramin was also a potent in vitro anticoagulant, and an group of anticancer agents." In fact, the recent encouraging results in vivo teratogen. Its clinical pharmacology and toxicology were, in with suramin as an antineoplastic agent have occurred as a result of retrospect, not understood well. decades of patient groundwork, followed by a few key observations in In 1979, DeClerq (7) appreciated that suramin could inhibit the patients with acquired immunodeficiency syndrome being treated activity of the reverse transcriptase found in RNA tumor viruses, such with suramin as part of a clinical therapeutic trial. The drug is highly as the murine leukemia. Moloney sarcoma, and avian myeloblastosis unusual, both in its biological properties and in the story of its devel viruses. For the latter, at least, the inhibition was competitive with opment as an antineoplastic agent. However, this story may have some (rA)n-oligodeoxythymidylate. These data were subsequently con valuable lessons to teach with respect to the identification of novel firmed by Basu and Modak (8). By 1984, Mitsuya, working in Brod- er's laboratory at the NCI,2 had noted that suramin could protect agents with potential antineoplastic activity. The history of suramin begins with the discoveries of Paul Ehrlich, uninfected T-cells from the cytopathic effect of HIV-1 (9); it was who had at his disposal the organic dyestuffs produced by the German presumed at the time that this was a consequence of reverse tran chemical industry from the coal tar wastes of Ruhr steel production scriptase inhibition. Because of these encouraging results and due to (3). He was faced with the problem of devising a treatment for African the dearth of active therapies for patients afflicted with AIDS, the drug trypanosomiasis, which was ravaging cattle herds and human popu entered clinical trials at several centers, including the NCI and the lations in what was then German East Africa. In the first few years of University of Southern California (10-13). the 20th century Ehrlich and Shiga discovered that certain bis-polysul In the fall of 1985, we began to care for patient B. H., who was infected with HIV-1 and had multiple cutaneous lesions of Kaposi's fonated naphthalene azo dyes, e.g., trypan red and try pan blue, were active antitrypanosomal agents. However, the activity of the dye com sarcoma. He had been receiving suramin therapy for approximately 1 pounds was not sufficient for veterinary use, and worse, the meat of year. B. H. was also suffering from Addison's disease; the older the cattle became discolored after treatment. On the basis of this early toxicology literature indicated that adrenocortical atrophy had indeed work, the Bayer company, probably responding to a military request been reported as early as 1937 (14) as a toxicity of suramin admin to stem an epidemic of equine trypanosomiasis during World War I istration to guinea pigs. Treatment of B. H. with appropriate gluco- (4), embarked on a search for an effective, colorless trypan derivative, and mineralocorticoids led to rapid relief of his symptoms, but his which culminated in 1916, when Ehrlich's former colleagues synthe treatment with suramin was halted. (The Kaposi's sarcoma then un derwent explosive growth, culminating in the patient's demise within sized suramin (Fig. 1) (5). It was given the name Bayer 205, among many other appellations, and by the early 1920s was known to be an 8 months from internal bleeding secondary to visceral disease.) active antitrypanosomal agent in bovine as well as human populations Suramin was eventually deemed to be ineffective treatment for HIV-1 (4). The unusual biological properties of this drug were recognized disease: improvement was noted neither in immunological function early on: "It does outlandish things to the cells and fluids of the human nor in clinical status. Significant toxicity was also discovered. How body," was the thought-provoking, although unrevealing comment of ever, because of the lack of understanding of the clinical pharmacol Paul DeKruif in his medical history Microbe Hunters, originally pub ogy of this agent, it was not at the time appreciated that due to the lished in 1926 (5). Widespread clinical use followed; the dose was 1 dosing schedule then used, toxicity could have been related to chron g weekly for 6 weeks. By 1947. it was appreciated that a cohort of ically elevated maximum achieved plasma suramin levels. Therapy Zairean patients with trypanosomiasis were also being cured of coin- for HIV patients was not individualized; plasma suramin levels were fection with onchocerciasis. Although more recently supplanted by batch-determined, sometimes months after patients were dosed. Sim other agents, suramin. by virtue of its cost, is still being used for its ilarly, no correlations were or could be drawn between the plasma original indication in poorer areas of the world. Only 4 years ago, a suramin area under the concentration curve and clinical or immuno traveler to the southern Sudan remarked to me on the use of suramin logical response. Furthermore, at the time of these trials (1985-1987). as an antiparasitic agent in the native population. individualized patient dosing by means of the Bayesian pharmacoki- Over the next several decades, an important body of literature had netic parameter value estimator, as developed by Lieberman et al. at been compiled which was summarized in a review compiled by the NCI (15) and Sher et al. ( 16) at the University of Maryland, was

Received 11/9/92; accepted 3/22/93. : The abbreviations used are: NCI. National Cancer Institute: HIV. human immuno The costs of publication of this article were defrayed in part by the payment of page deficiency virus; PKC, protein kinasc C; FGF, fibroblastic growth factor; bFGF. basic charges. This article must therefore be hereby marked advertisement in accordance with fibroblastic growth factor: PDGF, platelet derived growth factor; PSA. prostate specific 18 U.S.C. Section 1734 solely to indicate this fact. antigen; GAG, glycosaminoglycan; TGF. transforming growth factor; IGF. insulin-like ' C. A. S. is the recipient of an American Cancer Society Clinical Career Development growth factor; IC.so. 50^ inhibitory concentration; EGF, epidermal growth factor; EGFR. Award. Generous support from the Mathieson Foundation, the Du BÃ¶seHaywiird Foun epidermal growth factor receptor: IL. interlcukin: TNF-a. tumor necrosis factor a; LDL, dation, and the Florence and Herbert Irving Foundation has been received with gratitude. low density lipoprotein: FSH. follicle stimulating hormone; K-FGF. Kaposi's FGF. 2239

Fig. I. Structure of suramin (M, 1429), shown as the hexasodium salt. The compound was first syn NaO3S thesized in 1916. SO3Na S03Na SO3Na

NHCONH not available. This method, discussed below, has effectively elimi the survival probability at 1 year was 85%; while in all other groups, nated the majority of the Grade 3^4 toxicities associated with suramin it was 20%. Indeed, the median survival for the patients experiencing therapy in the prostate cancer population and may allow suramin to be the >75% drop in PSA has presently not been reached at 3.5 years. delivered to the HIV-infected population with reduced toxicity. Fur Pretreatment level of PSA was closely correlated with PSA response, thermore, at the time of the HIV trials, other potential mechanisms of 7 of 10 patients with pretreatment with PSA < 100 ng/ml experienced anti-HIV activity [e.g., inhibition of PKC kinase activity (17, 18)] a >75% decline with suramin treatment, but only 6 of 28 patients with were also not appreciated, nor was the potential of suramin for direct PSA >100 ng/ml experienced the same decline. The extent of pain antineoplastic activity. For example, it is now recognized that suramin relief was striking; 71% (15 of 21) of patients were able to reduce by is capable of binding to both K-FGF and basic FGF ( 19) and can block one-half or eliminate their use of narcotic analgesics. A similar trial of the binding of both to their respective receptors. This effect has been suramin in metastatic hormone refractory prostate cancer, carried out used to advantage by Moscatelli and Quarto (20) to inhibit the growth by Eisenberger et al.3 has confirmed the major features of the NCI and reverse the phenotype of fibroblasts transformed by these onco- trial and will be in press shortly. genes. These data suggest that suramin may be active in HIV-related However, the interpretation of the pain relief data is confounded by Kaposi's sarcoma, and a human trial is being planned, in which the the cotreatment of patients with hydrocortisone, required due to the suramin dosing will be adaptively controlled (16) to reduce toxicity. clinical adrenolytic effects of suramin. Hydrocortisone, alone, may The human adrenolytic properties of suramin were confirmed in the cause significant pain relief (24) and may cause transient decreases in HIV trial of Levine el al. (10). Historically, mitotane, an active agent PSA. Nevertheless, it is difficult to believe that the apparent prolon in adrenocortical cancer, had been discovered in a similar manner. gation of life in that cohort of patients that experiences a >75% Dogs that had been fed the insecticide DDT became Addisonian, and decline in PSA with suramin treatment (median survival not reached the active toxic principle was traced to the contaminant mitotane. Was at 3.5 years) is due merely to the hydrocortisone. Moreover, this it possible that suramin would behave similarly and would show apparent prolongation seems to confound the idea that suramin is only activity in adrenocortical cancer? By this time (1985) it had also been diminishing PSA production by the tumor but is doing little or nothing recognized that suramin could block the binding of at least one growth to prevent tumor growth. However, the characteristics of patients with factor (PDGF) to its receptor (21). Given the role of substances such metastatic prostate cancer accrued onto the several ongoing clinical as PDGF in the promotion of tumor cell growth, the possibility existed trials with suramin must be examined carefully so that proper com that suramin had potential application as an antineoplastic agent. The parisons among trials can be made: The data from the NCI trial clearly high affinity of suramin for a wide variety of biological targets was not indicate that the likelihood of achieving the >75% decline in PSA is daunting; it was, if anything, encouraging. It was, and remains, un inversely related to the PSA at presentation; i.e., the higher the PSA, the worse is the "response rate." Differences in response rates between clear if any active anticancer agent acts only by a single mechanism or at a single site, and a preponderance of evidence indicates that institutions may correlate with PSA levels at presentation, which in resistance would develop rapidly if that were the case. Might not turn may be a reflection of the biological aggressiveness of the tumor suramin, then, interrupt critical pathways in tumor cells at lower (as underscored by the tumor Gleason grade), the tumor bulk, or other, concentration than in normal cells? Thus it was that in 1985-1986, as yet undetermined factors. Implicitly, then, if the NCI data are with these, in retrospect, naive thoughts, that myself and C. E. Myers, confirmed, a case could be made for the earliest possible diagnosis of with clinical assistance from R. LaRocca, brazenly plunged forward recurrent prostate cancer, when presumably it would be the most into clinical trials with suramin in malignant disease. treatable by suramin. This might then be a major stimulus to ongoing studies using, e.g., monoclonal antibodies as imaging agents for mi Clinical Trials croscopic disease, and to the further development of "supersensitive"

Cancer of the Prostate. Hormone refractory metastatic prostate assays for PSA. The prospect of early diagnosis coupled with effective cancer patients have an average survival time of 30 weeks (22), and therapy for this refractory disease would indeed be an exciting one for the aggregate response to current chemotherapeutic agents is 7% (23). the clinical oncologist, but a great deal of work lies ahead to validate The first patient with hormone refractory metastatic prostate cancer these concepts. placed on suramin was R. M., who was entered as part of a general Cancer of the Adrenal Cortex. The original pilot trial with phase II trial. This patient, as were the 37 others in the NCI trial (1), suramin as an antineoplastic agent was conducted in patients with were treated by the continuous infusion schedule. Twenty-one patients adrenocortical cancer (25, 26). Patients were treated either with a had bone only disease, and 17 had measurable masses. Three of the 17 weekly i.v. bolus or by a constant infusion until the plasma suramin had complete resolution of measurable disease for 4, 5, and 11 level reached 300 ug/ml. Seventeen patients were available for re months. Three additional patients had a >50% radiographie reduction sponse; 11 of the 17 had previously been treated with mitotane. Two of their measurable disease. achieved a partial response, 2 had a minor response, and 5 had stable disease for 3-10 months. The remainder progressed. One of seven There was no radiographie resolution of bone lesions. However, 21 patients experienced a decline in serum PSA of >50%, and 13 expe rienced a decrease in PSA of >75%. In this latter group of patients, 3 M. Eisenberger et al., personal communication. 2240

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1993 American Association for Cancer Research. SURAMIN who had abnormally elevated plasma steroid hormone levels had a dominated by drug distributional clearance to organ sites, rather than 50% decline in multiple steroid precursors. An additional patient, who renal clearance. Plasma clearance has been modeled by a two com did not have radiographically demonstrable disease but who did have partment linear open process in which drug elimination occurs only elevated plasma aldosterone levels, hypertension, and hyperkalemia, from the central compartment. However, the variability in rate of drug became normotensive and normokalemic after suramin treatment. Re movement from the central to peripheral compartments (e.g., liver, sponses were observed predominantly in pulmonary mÃ©tastases.On spleen, kidney) is high, explaining the interpatient variability in the continuous infusion schedule used in these trials, the activity of plasma suramin level. This variability created a dosing problem be suramin in adrenocortical cancer was probably not greater than that of cause of the problem of suramin induced neurotoxicity (35). The mitotane, while toxicity was severe. The use of suramin as a thera neuropathy, which resembles the Guillain-BarrÃ©syndrome, occurs at peutic agent in this tumor must be reevaluated with the newer dosing plasma suramin levels exceeding 350 ug/ml and can be characterized schedules (see below). by profound motor weakness culminating in ventilatory failure. This Lymphoma. Suramin is active in lymphoid cell lines (27) and in suggested the need for individualized patient dosing based on mea chemotherapy resistant follicular lymphoma as well. Ten patients (28) surements of pharmacokinetic parameters and led to the development (nine Ã©valuable,seven with follicular mixed, and three with follicular, of the adaptive control strategy for suramin dosing (15, 16, 37). In small cleaved cell lymphomas) received suramin. Each had failed practice, prediction of plasma suramin levels were obtained on a from one to six other regimens. Five of the nine achieved partial minicomputer (ADAPT II software) by using the Bayesian algorithm, remissions. Sites of response included peripheral and central nodes, knowing the individual dosing history, and the plasma suramin levels spleen, skin, bilateral pleural effusions, and bone marrow, and some of at any given time. Then, the individual bolus dose was adjusted so that these responses were quite dramatic and remarkable for a single agent. the desired plasma suramin level was achieved at any future time Response duration varied from 3 to 9 months (median, 8 months). point. The adaptive control method of drug dosing ensured that plasma Follow-up of these initial interesting results is desperately needed, suramin levels did not rise above 350 ug/ml and eliminated the tox particularly given recent increases in the incidence of the disease. No icity of suramin induced Guillain-BarrÃ©syndrome as well as amelio clinical information exists on the use of suramin in large-cell lym rating many others. However, this method is quite cumbersome and phoma. may severely limit the widespread clinical application of this drug. It Other Tumors. Suramin did not have activity against metastatic has now become fairly clear that this stringent pharmacological mon renal cell cancer (29), except in one patient with Stauffer syndrome. itoring may not be necessary. Several clinical trials are now ongoing Interestingly, a renal cell line grown from another patient with met that eliminate the adaptive control algorithm entirely and replace it astatic renal cell cancer and Stauffer syndrome was also sensitive to with a fixed bolus schedule that mimics the computer generated dos the inhibitory effects of suramin (30). A preliminary report showed no ing scheme. Transient, extremely high (>400 ug/ml) plasma suramin evidence of response in 10 patients with advanced, platinum resistant levels may be reached after the initial bolus, but systemic toxicity appears to be minor.4 The establishment of a universally agreed upon ovarian cancer either (31), in spite of the recent demonstration of activity in ovarian cancer cell lines (32). However, prior to suramin dosing schedule will certainly hasten progress in resolving many issues surrounding the use of this agent. For example, should patients treatment. 6 of 10 patients had received 3 or more chemotherapeutic be treated to toxicity, or are "rest periods" between "cycles" more regimens. Of great interest would be a trial of i.p. suramin in refrac tory ovarian cancer. It is most likely that very high levels of suramin productive of higher response rates? What is the relationship between can be attained with little or no systemic toxicity. Furthermore, ma administered drug quantity, toxicity, and response? What is the min lignant cells can frequently be withdrawn via paracentesis and treated imum effective plasma level of suramin, and for what length of time prior to therapy; this may guide or help to individualize drug dosing. must it be maintained? Phase I trials are eagerly awaited. Potential Mechanisms of the Antitumor Effect A similar logic may be applicable to carcinoma in situ of the bladder. Extremely high levels of suramin may be obtained in this Inhibition of Growth Factor-Receptor Binding. Over the past hollow viscus by direct installation with little local and no systemic decade, it has become increasingly clear that suramin is, among its toxicity. other capabilities, able to function as a competitor of glycosaminogly- Clinical Toxicity of Suramin. This problem has been extensively can binding to a variety of targets. GAGs, while used in connective reviewed by Stein et al. (33). Major toxicities in the NCI prostate tissue and basement membrane as scaffolding material, are also the cancer study were: hematological (anemia, lymphopenia, thrombocy- substances that bind extracellular growth factors. Binding is compet topenia); renal; hepatic; hyperglycemia; skin rash; fatigue; fever; nau itive with respect to heparin, and perhaps with respect to suramin as sea; hypophosphatemia; adrenal insufficiency. Sixteen of 38 patients well. experience culture documented bacterial infections. Seventy-nine % The molecular weight of suramin is 1429, its structure is shown in of patients experienced NCI Cancer Treatment Evaluation Program Fig. 1. The six sulfonate groups are completely ionized at physiolog (CTEP) grade 1-2 peripheral sensory neuropathy. The coagulopathy ical pH. A common structural motif underlies the ability of suramin to (34) and motor neuropathy [Guillain-Barre-like syndrome (35)] seen bind to the heparin binding growth factors. This has been demon in the earlier trials could be prevented by careful monitoring of plasma strated by Baird et al. (38) who have found that two distinct, highly suramin levels. basic domains of 10-15 amino acids in the bFGF molecule have both Pharmacology. Early work by Collins et al. (36) demonstrated that heparin binding and growth stimulating activity. In fact, bFGF crys suramin was highly (99.7%) bound to plasma proteins and that the tallizes with a sulfate ion at what has been suggested is the heparin total body clearance is very low (0.41 ml/min). The rate of total body binding site (39). Rigidity of the ring bridging backbone is conferred clearance, predominantly via the kidney, displays little variation be by the presence of rotationally restricted polyamide and urea groups. tween individuals (coefficient of variation, 15%). The terminal half- These may lower the dissociation constant by diminishing the entropie life of the drug is 40-50 days. However, when the drug was given via component of binding to the growth factor target. However, detailed continuous infusion, a significant interpatient variability in plasma suramin levels was noted (16). The elimination of suramin from plasma, at least during the first few weeks of drug administration, is 4 N. Vogelzang, personal communication. 2241

kinetic and equilibrium studies on the binding of suramin to heparin These proteins all bear significant sequence homologies, and some binding growth factors have yet to appear. members of this group, including bFGF. are potent stimulators of Hosang et al. (40) was able to demonstrate that suramin could angiogenesis and neovascularization. For example. bFGF can stimu prevent the binding of PDGF to its cell surface receptors on fibro- late endothelial cell proliferation, as well as migration and invasive- blasts. This was correlated with decreased cellular proliferation. On ness (50). In addition. bFGF stimulates the growth of osteoblasts and the other hand, at least in glioma cell lines (41 ), blockade of PDGF- promotes their formation of calcium phosphate crystals in culture. receptor binding by suramin is not necessarily predictive of growth High levels of expression have been reported both in benign prostatic inhibition. In addition, at least one cell line not possessing measurable hyperplasia and in prostate carcinoma (51-55). bFGF. because it does PDGF receptors was still inhibited by suramin treatment, implying the not bear the appropriate leader sequence, is not secreted via the drug may be active by more than one mechanism. Similar data have classical secretory pathway and is thought to exert its effects via an been generated by Powis et al. (42) who used polyanionic growth internal autocrine loop, although this view has recently been chal factor binding organic dyes that are membrane impermeant. In Swiss lenged (50). Extracellular bFGF, on the other hand, is never found free 3T3 fibroblasts, blockade of growth factor-receptor binding could be but is complexed with glycosaminoglycans (e.g.. heparan sulfate) in demonstrated, but not cellular growth inhibition. basement membranes. In this context, suramin may behave as a GAG A series of interesting experiments have been performed in cells analogue, inasmuch as it binds to bFGF and blocks its binding to a transformed by the simian sarcoma virus (43^15). These cells express cellular receptor. the Mr 28.000 protein product of the \-sis oncogene, which is closely Inhibition by suramin of the bFGF effects on growth and DNA related to PDGF. It is frequently the case that the PDGF receptors, synthesis were first observed by Coffey et al. (48) in the mouse especially in simian sarcoma virus transformed cells, are not ex AKR-2B line and confirmed by others (19). The concentration of pressed in their mature form on the cell surface, but rather that PDGF suramin required for maximal effect was well within clinically achiev receptor binding occurs internally. Suramin. however, can block these able and tolerable plasma suramin levels (300 ug/ml). The initial internal autocrine loops as well as the external loops (45). Presumably cellular response of bFGF, the phosphorylation of a M, 90,000 protein, because of this ability to dissociate bound PDGF from its receptors, was blocked by suramin (56, 57). Moscatelli and Quarto (20), in 3T3 reversion to normal of the simian sarcoma virus transformed pheno- fibroblasts, reverted the bFGF transformed phenotype to normal with type in fibroblasts has been observed (46). suramin (1 ITIM).Similar effects were also observed in cells trans Suramin. because of its charge, is membrane impermeant. There formed by K-FGF. which appears to use the same receptor as bFGF fore, it must be actively transported into cells, and it is virtually certain (58). that cells will exert control over the rate of suramin internalization. The ability of suramin to block the binding of bFGF to its receptor The factors regulating this rate are currently unknown but may be suggests that the drug might be an antiangiogenic agent. Other data central to the ability of suramin to behave as a cytotoxic agent. The that suggest this possibility relate to the ability of suramin to bind to data presented above (46) provide evidence that suramin, which is a newly purified heparin binding growth factor, vasculotropin/ internalized probably predominantly via the processes of adsorptive vascular endothelial cell growth factor, a member of the PDGF family. endocytosis and/or fluid phase endocytosis or pinocytosis,5 is acces This protein stimulates the growth of human umbilical vein endothe sible to extralysosomal intracellular compartments. This is an impor lial cells and induces capillary cord formation. It can be dissociated tant finding, given the ability which most cells appear to have to from its receptor, to which it binds with picomolar K,,, by suramin exclude some polyanions (e.g.. try pan blue) which have structures that (59-61). Indeed, Wilks el a!. (62) and Gagliardi el al. (63) have are closely related to that of suramin. These data may imply that recently shown that suramin can replace heparin. in combination with suramin. after internalization, can also penetrate the endocytic vacu steroids in the chick embryo chorioallantoic membrane assay. De ole, but how this occurs is not known. pending on the assay system used, suramin may be angiostatic in the Sjolund and Thyberg (47) examined the effects of suramin in pri absence of added steroids. It is unknown at the current time whether mary cultures of smooth muscle cells. These cells produce PDGF inhibition of the neovascularization of solid tumors may related to the which promotes growth in an autocrine manner. Treatment with observed antineoplastic effects of this agent. suramin led to morphological transition from a normal contractile Other Growth Factors. Suramin also appears to be capable of state to a state in which myofilaments were lost and the amount of inhibiting the binding of IGF-1 (pi 9.2) to osteosarcoma cells in rough endoplasmic reticulum increased. This is the state of the smooth culture (64). but it is uncertain whether the effect occurs at the level muscle cell frequently seen in atheromas, and it is thus interesting to of the growth factor or of its receptor. This results in a dramatic speculate on the potentiation of these lesions in patients receiving decrease in cellular growth after 6 days. In nude mice, however, the long-term suramin therapy for nonmalignant disease. growth of osteosarcoma xenografts was markedly inhibited after PDGF is a heparin binding growth factor. There are many other transplant, and the effect persisted, during weekly suramin treatment, growth factors, some of which are known to be heparin binding, with for up to 100 days posttransplantation (65). IGF-II, while sharing 60% which suramin appears to be able to interact. For example, Coffey et homology with IGF-I, is slightly acidic (pi 6.5), but is probably al. (48) examined the effects of suramin on the mouse embryo AKR- heparin binding. It functions as an autocrine growth factor in the 2B, line, whose growth is sensitive to TGF-ÃŸand bFGF. and demon human rhabdomyosarcoma line RD and is at least partially displaced strated growth cessation and diminished tritiated thymidine incorpo from its receptor by suramin. This appeared to correlate well with ration in the presence of 100 UMsuramin. On the other hand. TGF-ÃŸ inhibition of cellular proliferation (66). Scatter factor, a heparin bind acts as a growth inhibitor in renal cell carcinoma lines. In the presence ing protein produced by nondifferentiating keratinocytes, has, in one of 300 ug/ml suramin, growth was restored almost to the control level of its subunits. amino terminal sequence homology with the smaller seen in the absence of drug (49). subunit of human hepatocyte growth factor. Scatter factor causes Another important group of heparin binding growth factors are the dispersal of epithelial cell colonies, but this effect was blocked at 250 family of fibroblast growth factors (FGF). The members of this group ug/ml of suramin (67). include acidic and basic FGF, int-2. K-FGF/hst, FGF 5, and FGF 6. Epidermal growth factor binds to heparin with only an extremely low affinity and in general is less sensitive to suramin than are growth 5 C. A. Stein and T. Munir, unpublished data. factors that demonstrate high affinity heparin binding (47). [In several 2242

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1993 American Association for Cancer Research. urothelial cell lines that are growth inhibited by suramin {e.g., T24, inhibitors of protein kinase C activity, including H7, dimethyl sulfox- where ICM) is 36 |JM, and HT 1376), however, EOF binding to its ide, staurosporine, and phosphorothioate oligodeoxynucleotides, also receptor is significantly more sensitive to inhibition by suramin than block internalization of fluid phase markers via the process of pinocy- it is in AKR-2B cells (68)]. In the A431 squamous carcinoma line, tosis, or fluid phase endocytosis. Free suramin, as well as suramin suramin was able to indirectly activate the EGFR by causing the bound transferrin, LDL, or albumin may enter cells by this process. release into the medium of TGF-a, which could then bind to EGFR, The inhibition of fluid phase endocytosis further blocks the ability of its natural receptor (69). The process of release by suramin of a rapidly dividing cells to obtain appropriate raw materials and may be mature, secreted, but cell surface bound growth factor has also been an additional growth suppressive mechanism. observed for the non-heparin binding murine protein, Wnt-1 [formerly Inhibition of Other Heparin Binding Proteins: Inhibition of int-1 (70,71)]. Glycosaminoglycan Metabolism. In plasma, suramin is >99% pro tein bound, mostly to albumin. The affinity is low [A",/approximately On the other hand, data concerning tumor cell growth stimulation 3 X 10~6 M (81)]. It is likely that hydrophobic interactions between by suramin was obtained by Olivier et al. (72), who noted low con centration (50-125 ug/ml) growth stimulation in 16 of 25 lines stud suramin and albumin (82) contribute to the stability of the complex. ied, including melanoma and osteosarcoma lines. A weak correlation After internalization, suramin is found in lysosomes (6, 83-85), existed between the number of EGFR per cell and the corresponding bound, perhaps, to lysosomal hydrolases, the functions of which it suramin ICM)values, but many lines without EGFR were also growth differentially inhibits. Brady and Constantopoulos and their cowork- stimulated. The stimulation of tumor growth at low suramin concen ers (86-90) have studied in detail the effects of suramin of those tration is of particularly great concern clinically, given the reliance of lysosomal hydrolases which are responsible for GAG catabolism. the older trials on continuous infusional methods of drug delivery. It They recognized that genetic defects in lysosomal enzymes are re strongly suggests that intermittent bolus dosing (which rapidly raises sponsible for a set of illnesses known as the lysosomal storage dis the plasma suramin level to the maximum tolerated dose), either by eases, or mucopolysaccharoidoses. In children thus afflicted, accumu fixed dose or by adaptive control monitoring as described above, lation of uncatabolized GAGs, such as the sulfates of heparan, should be the preferred method of treatment. dermatan, and chondroitin, in organs such as the brain, liver, spleen, Suramin is also capable of inhibiting the binding of IL-2 to both the and kidneys results in functional compromise. In experimental ani IL-2a and IL-2ÃŸreceptors (73). Subsequently, IL-2 induced receptor mals (91), the enzyme activities of the lysosomal enzymes iduronate phosphorylation and IL-2 induced proliferation are also blocked, with sulfatase, ÃŸ-glucuronidase, and hyaluronidase were consistently de cells becoming unable to enter S phase. In some cell lines, the effects creased after suramin treatment. This resulted from direct, although of suramin treatment could be entirely overcome by addition of ex non-competitive (with respect to GAG substrate), inhibition of these ogenous IL-2. However, relatively high levels of suramin ( 1 mg/ml) enzymes. Purified rat liver iduronate sulfatase was 100% inhibited at are required for these effects, and this is much higher than what can a suramin concentration of 50 UM.ÃŸ-Glucuronidase was not as sen be tolerated in human beings. IL-2 contains a nucleotide binding site sitive. However, the sensitivity of iduronate sulfatase to inhibition by (74) which may well be the suramin binding site as well (see below), suramin interferes critically with net GAG catabolism. This enzyme is and it is possible that this interaction causes a conformational change required for removal of the sulfate group on position 2 of the iduronic in the protein that prevents receptor binding. On the other hand, the acid residues of heparan and dermatan sulfates. If 2-O desulfation is binding of human TNF-a to cell surface receptors on K562 cells was inhibited, then the subsequent catabolic step, cleavage of the terminal blocked by suramin with a much lower IC50 (175 UM) (75). The glycosidase bond by a-t-iduronidase, will also be inhibited. Thus cytotoxic effects of human TNF-a in LM cells were also significantly highly sulfated, noncatabolized GAGs will accumulate in lysosomes ablated by suramin (<200 ug/ml). It is interesting to speculate that and, eventually, in the blood of patients. In effect, suramin treatment perhaps the improved sense of well-being experienced by many can induces an acquired mucopolysaccharoidosis syndrome that is remi cer patients within a short time of commencing suramin therapy niscent of Hunter disease, or mucopolysaccharoidosis II. The picture relates to a suramin induced decrease in the effective activity of is complicated by the fact that ÃŸ-glucuronidase can be inhibited by cachectin/tumor necrosis factor. Furthermore, high circulating levels suramin. This enzyme is required for cleavage of the ÃŸ-glucuronyl of TNF-a have been correlated with poor response to treatment with linkages found in chondroitin 4 and 6 sulfates, hyaluronic acid, and recombinant human a-interferon in chronic myelogenous leukemia, dermatan and heparan sulfates. Inhibition of this enzyme increases with severity of graft versus host disease, and with the development of plasma levels of all of these GAGs and resembles mucopolysaccha roidosis VII, also known as Hurler's disease. [Suramin will also cause venoocclusive disease and sepsis. The ability of suramin to block the binding of TNF-a to its receptor suggests additional clinical potential increases in levels of the gangliosides GM2, GM1, and GD1 (91, 92) by for this drug. inhibition of sialidases.] The uncatabolized GAGs accumulate in the Suramin can also inhibit the binding of transferrin to its receptor bloodstream, where they are weakly anticoagulating (93); in the cor (76). This may result in decreased cell growth, particularly in prostate nea of the eye (94), where they cause vortex keratopathy; and poten cancer metastatic to the bone (77), which seems to be highly depen tially in other organs as well. However, it is also possible that these dent on transferrin for growth. Apolipoprotein B, the heparin binding accumulated GAGs may have antineoplastic activity in their own protein component of LDL, a major cholesterol binding particle, is, right, by virtue of their ability to bind and sequester growth and like transferrin, also internalized via the process of receptor mediated angiogenic factors, to compete with extracellular matrix GAGs for endocytosis. LDL, too, is blocked from binding to its receptor by heparanases secreted by metastasizing tumors, and possibly to serve suramin (78). Furthermore, suramin can also inhibit other stages in the as regulators of nuclear function, all of which appear to be properties process of receptor mediated endocytosis. This includes inhibition of of suramin as well. the vacuolar H+-ATPase (79), the protein that acidifies organdÃes of The ability of suramin to inhibit lysosomal enzymes may have the vacuolar system, including the endosÃ³me. Lack of endosomal additional clinical toxicities. For example, hyperglycemia is now a acidification may result in lack of receptor-ligand dissociation and a well-recognized toxicity of clinical suramin treatment. In the mouse, subsequent decrease in receptor (e.g., transferrin receptor or LDL a pancreatic ÃŸ-isletlysosomal enzyme, acid amyloglucosidase, ap receptor) recycling back to the cell surface. Furthermore, we (80) have pears to affect levels of insulin secretion in mice (95-97). This en shown that in HL60 cells suramin, in a manner similar to that of other zyme was inhibited in a dose dependent fashion by suramin. The drug 2243

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1993 American Association for Cancer Research. also blocked the insulin response of the sulfonylurea secretogogue latter case, this may lead to decreased levels of phosphatidylinositol glibenclamide. which itself appears to act by blocking the ATP sen and phosphatidylinositides. This may decouple the cellular prolifera- sitive K f channel (98). Data of these kinds must be considered in tive response from a mitogenic signal derived, e.g., from growth factor planning the management of clinical suramin toxicity. stimulation. Related to this, Seewald et al. (108) have observed that Other Mechanisms of Antitumor Inhibition. Mammalian DNA suramin also appears to cause a decrease in the intracellular calcium polymerases are also heparin binding proteins, and suramin is able to response to growth factor binding; this may be in fact due to inhibition inhibit their function as well. The drug behaves like a double stranded of phosphoinositide synthesis (see below) and may augment suppres oligonucleotide analogue, exemplified by its ability to competitively sion of PKC activity, which is calcium dependent. These data suggest inhibit DNA polymerase a (a replicative polymerase) with respect to that suramin, like doxorubicin, may be an example of a self-syner- template-primer binding (99-101). The DNA primase activity associ gistic agent, i.e.. one which can act on sequential steps in an in-series ated with DNA polymerase a was also inhibited by suramin. but pathway. inhibition was competitive with respect to dGTP. Polymerases ÃŸ(the Diacylglycerol kinase. on the other hand, is a substrate for PKC, DNA repair polymerase) and 7, on the other hand, were somewhat and an enzyme necessary for the resynthesis of phosphoinositides. It more resistant to suramin treatment (27). Polymerase 8. which may be is also the enzyme that catalyzes the formation of phosphatidic acid, the leading strand DNA polymerase in eukaryotic cells, was inhibited a promoter of DNA synthesis and cellular growth ( 109). It appears to by suramin with ICM)= 36 \IM. do this, in part, by activating membrane bound G-proteins, which are The ability of suramin to compete with deoxynucleotide triphos- also sensitive to inhibition, in vivo by suramin (110). phates. especially ATP. for their binding sites may play a critical role An additional mechanism of action of suramin may involve inhi in the activity and toxicity of suramin. In work by Calcaterra et al. bition of nuclear DNA topoisomerase II (111). The drug can directly ( 102). the ATPase activity of submitochondrial particles was inhibited inhibit the ability of purified yeast topoisomerase II to relax super- by suramin, and the inhibition was also competitive with respect to coiled DNA. Because double stranded DNA is broken and rejoined in ATP binding. Indeed. Rago et al. ( 103) have suggested that disruption the process of strand passage, topoisomerase II becomes covalently of ATP generation by the mitochondrion may be one of the major lined to the 5' terminus of each strand. Several antineoplastic agents, mechanisms of cellular cytotoxicity in the DU 145 prostate carcinoma including amsacrine, doxorubicin, and etoposide, act by stabilizing cell line. Supporting this view are data (102) which demonstrate that this cleavable complex formed in the process of topoisomerase II suramin inhibits the submitochondrial adenine nucleotide translocase mediated DNA strand passage. In vitro, at 10 UM,suramin completely complex, which functions to transport AMP and ADP across the inhibited cleavable complex formation and inhibited amsacrine and mitochondria! membrane. Other examples of competition with deoxy etoposide induced cleavable complex formation. Moreover, suramin nucleotide triphosphates are also known (104). does appear to enter the nucleus of hamster fibroblast cells and, at 50 Of potentially great significance are recent observations that UM,can decrease the number of protein linked DNA strand breaks suramin has been shown to competitively inhibit the phosphorylating produced by amsacrine. These data suggest that combination therapy ability of PKC (isoforms I. II, and III, encoded by the 7. ÃŸ.and a with suramin and a topoisomerase II inhibitor would not be success genes, respectively) with respect to ATP (17, 18). Moreover, the ful. inhibition demonstrated a degree of isoform specificity, with the order of inhibition being I > II = III. Phorbol ester induced PKC activation Selected Preclinical Studies was also blocked in the presence of suramin. Furthermore, at low suramin concentration (<50uM). in the presence of calcium, but in the Prostate Cancer. Studies with suramin in prostate cancer lines in absence of required lipid cofactor stimulation, suramin actually stim vivo demonstrate that the cytotoxic effects are both highly concentra ulated PKC activity by as much as 300%. Stimulation of activity was tion and cell line dependent. For example ( 112), at < 100 UM,suramin also isoform dependent, with I > II > III. We6 have recently shown stimulated the growth of the MLL subline of the rat Dunning R3327 that these biphasic concentration dependent effects on PKC phospho tumor; while at higher concentrations, cell growth was inhibited. In rylating ability are not confined to suramin alone but also occur with the PC3, DU 145. and AT2 lines; and in prostatic tumor expiants, no other bis(polyanionic) compounds containing hydrophobic bridges. effect on growth was found at low suramin concentration, while However. PKC is a critical intracellular enzyme involved in many growth inhibition occurred at higher concentration. transmembrane signaling events and may also be involved in tumor Kim et al. (113) have shown that significant inhibition of androgen promotion (105). The unusual biphasic response to suramin and other independent DU145 cells by suramin (100 or 300 ug/ml) required bis(polyanions) may be a critical factor in determining tumor response approximately 5 days. Cells appeared to be blocked in S phase. Both to alternative drug dosing schedules. In addition, the complexity of the this line and the PC3 line contain EOF receptors and secrete growth i/i vitro actions of suramin, as exemplified by its interactions with promoting TGF-a, which is its natural ligand. Binding of TGF-a to its PKC, tend to invalidate overly simplistic explanations for its in vivo receptor was blocked by suramin at 400 ug/ml. and this correlated activity. For example, it has been assumed that the cytoprotective with decreases in cell growth that were partially overcome by treat effects of suramin against HIV-1 are due to the ability of the drug to ment with exogenous TGF-a. The ability of TGF-a to only partially inhibit the HIV-1 reverse transcriptase. However, Fields et al. (106) overcome the effects of suramin indicates that multiple growth inhib have recently shown that the PKC inhibitor H7 (an isoquinoline itory mechanisms may be active. The androgen dependent line LNCaP sulfonamide) also reduces HIV-1 infectivity, possibly by blocking was somewhat more sensitive to the cytostatic effects of suramin HIV-1 induced phosphorylation of CD4 by PKC. Suramin. which at a (114), perhaps because of increased cellular retention of the drug higher concentration is a potent PKC inhibitor, may inhibit HIV-1 relative to the DU145 line (115). In the LNCaP cells, growth was replication via this cytoprotective pathway. arrested in the G()-G| phase of the cell cycle (116). In androgen Alteration of signal transduction pathways by suramin is not limited dependent DDT-1 cells, suramin (

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1993 American Association for Cancer Research. Peehl ei al. (117) used an in vitro explant system for culturing suramin (130). Carcinoembryonic antigen appears to be anchored to prostate cells taken from radical prostatectomies in patients with nor the cell membrane by a glycane phosphatidylinositol. Analogous ob mal, hyperplastic, or cancerous prostates. At concentrations ranging servations have been made (131, 132) on the ability of suramin, in the from 0 to 50 ug/ml, suramin inhibited growth of the cells taken from rat C6 glioma line, to prevent the labilization, from the cell surface, of the hyperplastic and cancerous prostates but not from the normal an isoform of the glycane phosphatidylinositol anchored N-CAM. prostates. The antiproliferative effect was transient and disappeared Inhibition of the Metastatic Phenotype. Because of the ability of after 24 h, even at a suramin concentration of 500 ug/ml. Additional suramin to inhibit the activity of lysosomal GAG catabolic enzymes, experiments designed to evaluate the effects of suramin on normal it is reasonable to expect that the drug could inhibit extracellular prostate tissue were designed by Morton el til. (118). They castrated heparanases as well. Nakajima. et al. (133) showed that melanoma normal male Copenhagen rats and after 10 days treated them with heparanase (an endo-ÃŸ-u-glucuronidase) could be noncompetitively testosterone and suramin or protamine. No inhibition of prostate re inhibited by suramin. Suramin also inhibited the degradation of sub- generation occurred with either. However, both inhibited the growth endothelial basement membrane by B16 melanoma cells, and inhib of s.c. implanted AT-2 prostate cells. ited invasion. However, no effects on B16 cell growth were observed, Suramin may also affect circulating levels of gonadotropins (118, suggesting a decoupling between an increase in cell number and 119). In rats receiving the drug, plasma testosterone fell to castrate metastatic potential. Other sulfated glycoconjugate-binding molecules levels. This was not associated with a drop in luteinizing hormone, but in the metastatic process include laminin and thrombospondin. These FSH did fall, suggesting inhibition of gonadotropin release at the level proteins are found in the extracellular matrix and appear to mediate of the pituitary (118, 120). Furthermore, suramin could also inhibit the cell attachment, spreading, and migration (134). Suramin, at physio binding of FSH to its cell surface receptor at a concentration (about 10 logically attainable plasma concentrations, could inhibit the binding of UM)that was similar to that observed for suramin mediated inhibition thrombospondin to sulfatide. The binding of laminin was also inhib of FSH-stimulated steroidogenesis in Sertoli cells. Other direct effects ited, but at a higher concentration. Melanoma cell adhesion and on the testes included suppression of luteinizing hormone/human chemotactic migration in response to thrombospondin and laminin chorionic gonadotropin stimulated steroidogenesis. were also suppressed. Prostate cancer cell (LNCaP) motility, an im Breast Cancer. Eisenberger and Fontana (121) have recently dis portant property of metastasizing cells, is suppressed by suramin (112) cussed literature data that indicate that a variety of growth factors, and may be restored by addition of bFGF. The use of suramin as an including FGF. TGF-a, IGF-I. and IGF-II. may be potent mitogens for antimetastatic agent in clinical trials has yet to be explored but, on the breast carcinoma cells and may act in an autocrine or paracrine factor. basis of the preclinical data, may be a most promising field of en Cullen eral. (122), demonstrated that PDGF. secreted by breast tumor deavor. cells that do not bear the PDGF receptor, may bind to stromal cells and Conclusions increase their production of IGF-I, which, as mentioned above, is mitogenic for the breast tumor cells. In estrogen receptor positive There can be little doubt of the ability of suramin to affect cellular MCF7 cells, suramin (>100 UM)could inhibit growth stimulated by biology and physiology. However, at the present time, it is probably IGF-I, as well as by EGF. 17ÃŸ-estradiol,and cathepsin D (123). The not prudent to claim that the drug exerts its antiproliferative properties latter, a lysosomal enzyme, may help promote breast cancer invasion by any single mechanism. The specific mechanism of cellular growth and metastasis. At lower suramin concentrations, suramin increased inhibition (Â«'.#..blockade of growth factor-receptor binding) is prob the mitogenic activity of EGF and cathepsin D. This biphasic response ably highly tissue type dependent. By extension, different mechanisms to suramin has also been observed in several other breast cancer lines of action may be relevant in different cells, although it is difficult to (124). Estrogen receptor negative cell lines (MDA MB 231, SK-BR- predict which on an a priori basis. Furthermore, critical determinants 3), were particularly sensitive to the cytostatic effects of suramin (50<7r of the mechanism, such as rates of drug intracellular internalization inhibitory dose, MDAMB231. 7 UM;MCF7, 50 UM).Clinical trials of and subcellular compartmemalization, are currently poorly under suramin in single treatment failure metastatic breast cancer are to stood. Studies designed to examine the cellular pharmacology of begin soon at the University of Maryland. suramin will help in the determination of which of the many intra Colon Cancer. An interesting example of the ability of suramin to cellular targets of suramin are relevant to its antineoplastic effects. regulate cellular growth and differentiation is found in the work of Whether the drug itself will eventually become part of the therapeutic Fantini et al. (82, 125-129). These authors have investigated the armamentarium is also not clear, although the initial trials are encour effects of suramin on the growth and differentiation of the HT29-D4 aging. Many difficulties, including the optimum dosing schedule, colonie adenocarcinoma line. These cells undergo differentiation in must be worked out. Finally, the imagination of synthetic organic galactose containing, glucose free media. In the presence of 100 ug/ml chemists must be directed toward improving the activity of this agent. suramin. the cells became organized into a polarized monolayer of Suramin analogues will also be useful in clarifying which targets are columnar cells, became antisucrase antibody reactive, and expressed truly relevant ones. We anticipate great progress in this direction in the alkaline phosphatase and isomaltase. which are normal brush border near future. hydrolases. Differentiation may have occurred because of the ability of suramin to block the binding of IGF-I (IC5(, 25 ug/ml). a postulated Acknowledgments autocrine growth factor for this cell line, to its receptor (128). A The author gratefully acknowledges the encouragement he received from V. suramin analogue. NF036 ( 130). was able to induce HT29-D4 differ DeVita. C. E. Myers. J. Folkman. and S. Broder. entiation but did not affect lysosomal morphology ( 127). This result is highly significant because NF036 contains only a single naphthalene References trisulfonate moiety and is much less likely to bind to growth factors with high avidity. Structure-activity studies of this type will be of great 1. Myers. C.. Cooper. M.. Siein. C.. LaRocca. R.. Wallher. M.. Weiss. G.. Choyke. P.. Dawson. N.. Steinberg. S.. Llhrich. M.. Cussidy. J., Kohler. K.. Trepel. J.. and Linehan. help in defining relevant targets for suramin and its analogues. W. Surumin: a novel growth factor antagonist with activity in hormone-refractory Levels of secreted tumor markers may also be affected by suramin. metastatic prostate cancer. J. Clin. Oncol.. 10: 881-889, 1992 Carcinoembryonic antigen, which is normally released from HT29-D4 2. Pinedo. H., and van Rijswijk. R. Suramin awakes? J. Clin. Oncol.. 10: 875-877. 1992 3. Borkin. J. The Crime and Punishment of I. G. Farben, p. 5. New York: The Free Press, cells during differentiation, was not released in the presence of 1978 2245

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Significance of the increased frequency of regulation of platelet-derived growth factor receptors. Proc. Nail. Acad. Sci. USA, 81: selective cortical necrosis of the adrenal as a cause of Addison's disease. JAMA, 109: 7466-7470. 1984 490-493, 1937 44. Keating. M.. and Williams. L. Autocrine stimulation of inlracellular PDGF receptors 15. Lieberman, M.. Katzper. M., Cooper. M.. LaRocca, R., Uhrich. M., Cassidy. J.. in v-j/i-lransformed cells. Science (Washington DC). 239: 916-916. 1988 Myers. C.. and Peck. C. Nonmember population pharmacokinetic analysis and Baye- 45. Huang. S., and Huang. J. Rapid turnover of the piÃ¡lele!derived growlh faclor receplor sian forecasting during suramin therapy in prostate cancer: one versus two compart in .Ã¯/.v-transformedcells and reversal by suramin. J. Biol. Chem., 26.?: 12608-I26I8. ment PK models. Proc. Am. Soc. Clin. Oncol.. 9: 262, 1990 1988 16. Scher, H.. Jodrell, D.. Iversen, J., Curley, T., Tong, W.. Egorin, M., and Forrest, A. Use 46. 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