Suramin: a Novel Antineoplastic Agent with Multiple Potential Mechanisms of Action1
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[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 BöseHaywiird 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 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1993 American Association for Cancer Research. NaO3S NHCO CH3 H3C CONH SO3Na 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.