Review of Advances in Uroprotective Agents for Cyclophosphamide- and Ifosfamide-induced Hemorrhagic Cystitis
2016; Elsevier BV; Volume: 100; Linguagem: Inglês
10.1016/j.urology.2016.07.030
ISSN1527-9995
Autores Tópico(s)Acute Lymphoblastic Leukemia research
ResumoCyclophosphamide and ifosfamide are widely used drugs for malignancies and rheumatologic conditions. One of the most significant adverse reactions to these drugs is hemorrhagic cystitis. Mesna is the most widely used uroprotective agent that acts to neutralize the caustic metabolite, acrolein, responsible for induction of hemorrhagic cystitis. However, mesna is not a perfect alternative, and studies since its discovery have investigated the use of alternative drugs and adjuncts to increase mesna's efficacy. This review details some of the recent work into novel uroprotective agents for drug-induced hemorrhagic cystitis. Cyclophosphamide and ifosfamide are widely used drugs for malignancies and rheumatologic conditions. One of the most significant adverse reactions to these drugs is hemorrhagic cystitis. Mesna is the most widely used uroprotective agent that acts to neutralize the caustic metabolite, acrolein, responsible for induction of hemorrhagic cystitis. However, mesna is not a perfect alternative, and studies since its discovery have investigated the use of alternative drugs and adjuncts to increase mesna's efficacy. This review details some of the recent work into novel uroprotective agents for drug-induced hemorrhagic cystitis. Cyclophosphamide and ifosfamide (Figure 1, Figure 2) are oxazaphosphorine agents approved by the Food and Drug Administration (FDA) for use against a number of malignancies and benign diseases. Cancers treated with cyclophosphamide or ifosfamide include both childhood and adult onset. Cyclophosphamide and ifosfamide are prescribed for pediatric cancers including acute lymphoblastic leukemia, neuroblastoma, and retinoblastoma. Minimal-change nephrotic syndrome is treated with cyclophosphamide. In adults, cyclophosphamide is approved for use in acute myelogenous leukemia, breast cancers, chronic lymphocytic leukemia, Hodgkin's lymphoma, multiple myeloma, mycosis fungoides, non-Hodgkin lymphoma, and ovarian adenocarcinoma. Cyclophosphamide also has a role as an immunosuppressant in hematopoietic stem cell transplantation.1FDA Cyclophosphamide for injection.http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdfGoogle Scholar, 2NIH National Cancer Institute Cyclophosphamide.http://www.cancer.gov/about-cancer/treatment/drugs/cyclophosphamideGoogle Scholar Moreover, ifosfamide is FDA-indicated for use against testicular germ cell tumors.3FDA IFEX.http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019763s016lbl.pdfGoogle Scholar It has therapeutic efficacy in small-cell and non–small cell lung cancers, bladder cancer, non-Hodgkin lymphoma, and advanced breast cancer.4Siu L.L. Moore M.J. Use of mesna to prevent ifosfamide-induced urotoxicity.Support Care Cancer. 1998; 6: 144-154https://doi.org/10.1007/s005200050149Crossref PubMed Scopus (41) Google Scholar As demonstrated above, the use of these oxazaphosphorine drugs is wide and encompasses a vast number of patients. Based on American Cancer Society estimates of cancer incidence, the incidence of neoplasms with an FDA indication of cyclophosphamide is more than 400,000 new patients a year.5American Cancer Society Cancer Facts and Figures.2016Google ScholarFigure 2The chemical structure of ifosfamide.35National Center for Biotechnology Information PubChem Compound Database; CID=3690.https://pubchem.ncbi.nlm.nih.gov/compound/3690Google Scholar (Color version available online.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Hemorrhagic cystitis is a sterile, noninfectious cystitis primarily induced by ifosfamide and cyclophosphamide. Ifosfamide may be particularly prone to inducing this complication.6Klastersky J. Side effects of ifosfamide.Oncology. 2003; 65: 7-10https://doi.org/10.1159/000073351Crossref PubMed Scopus (83) Google Scholar Cyclophosphamide, as a cause of hemorrhagic cystitis, was first described by a German group in 1958 and later examined by Watson and Notley in 1973.7Arnold H. Bourseaux F. Brock N. Neuartige Krebs-Chemotherapeutika aus der Gruppe der zyklischen N-Lost-Phosphamidester.Naturwissen-Schaften. 1958; 45Crossref Scopus (60) Google Scholar, 8Brock N. Pohl J. Asta-Werke AG Degussa Pharma GruppeThe development of mesna for regional detoxification.Cancer Treat Rev. 1983; 10: 33-43Abstract Full Text PDF PubMed Scopus (72) Google Scholar They noted that 10%-40% of patients on cyclophosphamide developed hemorrhagic cystitis, which sometimes abated on the withdrawal of the offending agent.9Watson N.A. Notley R.G. Urological complications of cyclophosphamide.Br J Urol. 1973; 45: 606Crossref PubMed Scopus (82) Google Scholar In 1 study on the use of cyclophosphamide in rheumatic disease, Yilmaz et al found that of 1018 patients, about 1.5% developed hemorrhagic cystitis.10Yilmaz N. Emmungil H. Gucenmez S. et al.Incidence of cyclophosphamide-induced urotoxicity and protective effect of mesna in rheumatic diseases.J Rheumatol. 2015; 42: 1661-1666https://doi.org/10.3899/jrheum.150065Crossref PubMed Scopus (37) Google Scholar In a 1975 study of children treated with cyclophosphamide for leukemia, 25 cases of hemorrhagic cystitis were observed among 314 patients.11Lawrence H. Simone J.A.R. Hemorrhagic cystitis in children with leukemia.Cancer. 1975; 36: 1572-1576Crossref PubMed Scopus (42) Google Scholar Cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis remains an important clinical problem today. In general, mild hemorrhagic cystitis can be managed on an outpatient basis with hydration and is transient in nature. Moderate hemorrhagic cystitis can require clot extraction via cystoscopy, continuous bladder irrigation, and instillation of agents into the bladder. Severe hemorrhagic cystitis can require inpatient management with transfusions and major procedures, including cystectomy. Some of the molecular mechanisms of cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis have been defined, and therapeutic targets may exist within these pathways. During hepatic metabolism of cyclophosphamide and ifosfamide, acrolein is generated, filtered by the kidneys, and concentrated in the bladder. This metabolite causes a pyroptotic reaction in the bladder urothelium that in turn leads to ulceration. Acrolein induces cell death through upregulation of reactive oxygen species (ROS). Acrolein also activates inducible nitric oxide synthase, leading to the production of nitric oxide.12Souza-Fiho M.V. Lima M.V. Pompeu M.M. Ballejo G. Cunha F.Q. Ribeiro R.D.A. Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis.Am J Pathol. 1997; 150: 247-256http://www.ncbi.nlm.nih.gov/pubmed/14634459PubMed Google Scholar, 13Korkmaz A. Oter S. Deveci S. et al.Involvement of nitric oxide and hyperbaric oxygen in the pathogenesis of cyclophosphamide induced hemorrhagic cystitis in rats.J Urol. 2003; 170: 2498-2502https://doi.org/10.1097/01.ju.0000085593.31396.d8Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Both ROS and nitric oxide produce peroxinitrates, which attack lipids and proteins.14Korkmaz A. Oter S. Sadir S. et al.Peroxinitrite may be involved in bladder damage caused by cyclophosphamide in rats.J Urol. 2005; 173: 1793-1796https://doi.org/10.1097/01.ju.0000154344.80669.e3Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar They are also responsible for breaking DNA strands, ultimately resulting in cessation of protein production.15Korkmaz A. Topal T. Oter S. Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation.Cell Biol Toxicol. 2007; 23: 303-312https://doi.org/10.1007/s10565-006-0078-0Crossref PubMed Scopus (207) Google Scholar ROS production induces transcription factors including NF-κB and activator protein 1, which stimulate proinflammatory cytokine (tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1β]) gene expression.16Keles I. Bozkurt M.F. Cemek M. et al.Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna.Int Urol Nephrol. 2014; 46: 2301-2310https://doi.org/10.1007/s11255-014-0833-8Crossref PubMed Scopus (25) Google Scholar Thus, cyclophosphamide and ifosfamide induce hemorrhagic cystitis through various cascades, which converge on acrolein and its effects. Once cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis has occurred, there are a few good treatment options. These options include continuous bladder irrigation, aluminum potassium sulfate and formalin instillation, fulguration, hyperbaric oxygen, and in extreme cases, cystectomy. Intravesical infusion of aluminum potassium sulfate and formalin acts as chemical corrosives causing coagulation through protein precipitation and protein hydrolysis, respectively.17Haldar S. Dru C. Bhowmick N. Mechanisms of hemorrhagic cystitis.Am J Clin Exp Urol. 2014; 2: 199-208PubMed Google Scholar Hyperbaric oxygen can cause vasoconstriction and fibrosis.18Rajaganapathy B.R. Jayabalan N. Tyagi P. Kaufman J. Chancellor M.B. Advances in therapeutic development for radiation cystitis.Low Urin Tract Symptoms. 2014; 6: 1-10Crossref PubMed Scopus (14) Google Scholar Moreover, none of these treatment options is completely efficacious. In short, prevention of cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis is preferred over treatment of established disease. An important agent that protects against cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis is mesna. In 1983, Brock and Pohl defined the mechanism of action of mesna and its potential use as a uroprotective agent with concurrent use of cyclophosphamide.8Brock N. Pohl J. Asta-Werke AG Degussa Pharma GruppeThe development of mesna for regional detoxification.Cancer Treat Rev. 1983; 10: 33-43Abstract Full Text PDF PubMed Scopus (72) Google Scholar Mesna (sodium-2-mercaptoethanesulfonate) (Fig. 3) is a thiol compound that is metabolized to dimesna and excreted by the kidneys. The reabsorbed portion is acted on by glutathione dehydrogenase and generates free sulfhydryl groups, which binds acrolein in the bladder, leading to effective excretion.4Siu L.L. Moore M.J. Use of mesna to prevent ifosfamide-induced urotoxicity.Support Care Cancer. 1998; 6: 144-154https://doi.org/10.1007/s005200050149Crossref PubMed Scopus (41) Google Scholar, 6Klastersky J. Side effects of ifosfamide.Oncology. 2003; 65: 7-10https://doi.org/10.1159/000073351Crossref PubMed Scopus (83) Google Scholar Throughout the years, varying dosages and timings of mesna and hyperhydration have been tested as prophylaxis against hemorrhagic cystitis. In 2002, the American Society of Clinical Oncology established clinical practice guidelines for the use of mesna. These guidelines suggest that for a standard dose of ifosfamide 150 mL/h. They determined that hyperhydration is a safe and inexpensive preventative measure for hemorrhagic cystitis in patients treated with cyclophosphamide for bone marrow transplantation.21Ballen K. Becker P. Levebvre K. et al.Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in bone marrow transplant recipients.Oncology. 1999; 57: 287-292http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.online.karger.com/library/karger/renderer/dataset.exe?jcode=OCL&action=render&rendertype=fulltext&uid=OCL.ocl57287\npapers2://publication/uuid/1F060135-96E1-4084-9ADA-6D0F6ECAF856Crossref PubMed Scopus (26) Google Scholar However, hyperhydration may not be possible in patients with renal, lung, or liver dysfunction because of risks of fluid overload.20Shepherd J.D. Pringle L.E. Barnett M.J. Klingemann H.-G. Reece D.E. Phillips G.L. Mesna versus hyperhydration for the prevention of cyclophosphamide- induced hemorrhagic cystitis in bone marrow transplantation.J Clin Oncol. 1991; 9: 2016-2020Crossref PubMed Scopus (139) Google Scholar In a 2003 article, Mank et al discussed the dangers of fluid overload in patients where hyperhydration is used and the need for daily weights to assess fluid status.22Mank A. Semin-Goossens A. Lelie J.V.D. Bakker P. Vos R. Monitoring hyperhydration during high-dose chemotherapy: body weight or fluid balance?.Acta Haematol. 2003; 109: 163-168https://doi.org/10.1159/000070964Crossref PubMed Scopus (21) Google Scholar Thus, hyperhydration is not an ideal alternative to mesna. Moreover, mesna has not been a panacea for hemorrhagic cystitis. Yilmaz and colleagues determined that within their cohort of patients treated with cyclophosphamide for rheumatic diagnoses there was no uroprotective effect of mesna (1.53% rate of hemorrhagic cystitis with mesna treatment vs 1.8% without mesna, P = .08).10Yilmaz N. Emmungil H. Gucenmez S. et al.Incidence of cyclophosphamide-induced urotoxicity and protective effect of mesna in rheumatic diseases.J Rheumatol. 2015; 42: 1661-1666https://doi.org/10.3899/jrheum.150065Crossref PubMed Scopus (37) Google Scholar In addition, mesna has been associated with significant adverse effects. In 2007, Khaw et al reported a hypersensitivity-like cutaneous and systemic reaction to mesna.23Khaw S. Downie P. Waters K. Ashley D.H.J. Adverse hypersensitivity reactions to mesna as adjunctive therapy for cyclophosphamide.Pediatr Blood Cancer. 2007; 49: 341-343Crossref PubMed Scopus (22) Google Scholar Subsequently, in 2007, Lima et al examined the histologic changes of the mesna- and ifosfamide-exposed bladder. They found that even with 3 doses of pretreatment mesna, 66.7% of patients showed pathologic changes of the bladder wall during cystoscopy and all exhibited microscopic lesions such as edema, exocytosis, and hemorrhage. Therefore, even with standard regimens of mesna prophylaxis, there are urothelial and mucosal changes following ifosfamide exposure.24Lima M.V.A. Ferreira F.V. Macedo F.Y.B. De Castro Brito G.A. Ribeiro R.A. Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis.Cancer Chemother Pharmacol. 2007; 59: 643-650https://doi.org/10.1007/s00280-006-0307-5Crossref PubMed Scopus (31) Google Scholar Clearly, there is a need for alternative uroprotective agents. Many uroprotective agents have shown promising results in animal models but have not transitioned to clinical trials. Keles et al described the use of resveratrol, a grape derivative with antioxidant effects, to ameliorate the effects of cyclophosphamide-induced ROS in the bladder. They demonstrated that 20 and 40 mg/kg of resveratrol conferred both biochemical and histopathologic protective effects against cyclophosphamide-induced hemorrhagic cystitis. However, when compared with mesna, the results were inferior.16Keles I. Bozkurt M.F. Cemek M. et al.Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna.Int Urol Nephrol. 2014; 46: 2301-2310https://doi.org/10.1007/s11255-014-0833-8Crossref PubMed Scopus (25) Google Scholar Leite et al used anakinra, an IL-1 receptor blocker, and infliximab, a TNF inhibitor, to attenuate cyclophosphamide-induced hemorrhagic cystitis in rodents. They found that anakinra controlled hemorrhage and mitigated inflammatory and functional bladder parameters. However, infliximab failed to show significant benefit. They postulated that infliximab's failure was due to TNF signaling through only the TNFR2 receptor. TNF signaling in the bladder is transduced through the TNFR1 and TNFR2 receptors. TNFR1 and TNFR2 signaling are associated with cell death and survival, respectively.25Leite C.A.V.G. Alencar V.T.L. Melo D.L.R. et al.Target inhibition of IL-1 receptor prevents ifosfamide induced hemorrhagic cystitis in mice.J Urol. 2015; 194: 1777-1786https://doi.org/10.1016/j.juro.2015.07.088Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar These findings point to the complexity of cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis. The molecular intricacy of chemotherapy-induced hemorrhagic cystitis is also highlighted by the multifaceted involvement of proinflammatory immune responses. For instance, the mitogen-activating kinases (MAPKs) potentiate the proinflammatory response triggered by cyclophosphamide and ifosfamide. In 2015, Kim et al described that ROS produced by acrolein in the bladder activate MAPKs. Diallyl disulfide (DADS) produced from garlic oil increases the antioxidant enzymatic activities that scavenge ROS. DADS also acts as an anti-inflammatory mediator by downregulating MAPK signaling pathways and NF-κB. They demonstrated that DADS inhibits cyclophosphamide-induced hemorrhagic cystitis by suppressing urine inducible nitric oxide synthase and cyclooxygenase 2 protein expression in the bladder, thereby attenuating ROS-induced damage.26Kim S.H. Lee I.C. Ko J.W. et al.Diallyl disulfide prevents cyclophosphamide-induced hemorrhagic cystitis in rats through the inhibition of oxidative damage, MAPKs, and NF-κB pathways.Biomol Ther (Seoul). 2015; 23: 180-188https://doi.org/10.4062/biomolther.2014.126Crossref PubMed Scopus (41) Google Scholar Abo-Salem explored the use of pentoxifylline, a nonspecific phosphodiesterase inhibitor that downregulates proinflammatory cytokines, as a potential prophylactic for chemotherapy-induced hemorrhagic cystitis. This work concluded that pentoxifylline reduces cyclophosphamide-induced hemorrhagic cystitis through antioxidant and anti-inflammatory effects.27Abo-Salem O. Uroprotective effect of pentoxifylline in cyclophosphamide-induced hemorrhagic cystitis in rats.J Biochem Mol Toxicol. 2013; 27: 343-350Crossref PubMed Scopus (14) Google Scholar In conclusion, numerous proinflammatory pathways initiated by cyclophosphamide and ifosfamide may be therapeutic targets for hemorrhagic cystitis. Understanding that proinflammatory cytokines have an important influence on the development of hemorrhagic cystitis, Vieira et al directed their work to reduce or block these actions. They first investigated the effect of glucocorticoids on the release of proinflammatory cytokines. Dexamethasone was used both as monotherapy and as an adjunct to mesna to determine bladder effects. They determined that replacing 1 or 2 doses of mesna with dexamethasone was as effective as an entire series of mesna. However, dexamethasone as monotherapy was not inferior, and glucocorticoids as a class have contraindications with certain cancers, whereby influencing response to treatment.28Vieira M.M. Macêdo F.Y. Filho J.N. et al.Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats.Phytother Res. 2004; 18: 135-141Crossref PubMed Scopus (30) Google Scholar Macedo, an investigator from the above publication, and his colleagues recently examined the role IL-4 plays as a modulator to the proinflammatory cascade and its potential role in cyclophosphamide-induced hemorrhagic cystitis. IL-4 inhibits monocyte-derived cytokines, such as IL-1B, IL-6, IL-8, and TNF. IL-4 can also reduce the induction of cyclooxygenase 2, which subsequently inhibits prostaglandin release. They determined that IL-4 was produced in greater amounts after ifosfamide administration and that intraperitoneal injection of IL-4 reduced both edema and hemorrhage in the bladder. However, IL-4 was effective only at high doses, possibly because of its binary effects on both pro- and anti-inflammatory cascades.29Macedo F.Y.B. Mourão L.T.C. Freitas H.C. et al.Interleukin-4 modulates the inflammatory response in ifosfamide-induced hemorrhagic cystitis.Inflammation. 2012; 35: 297-307https://doi.org/10.1007/s10753-011-9319-3Crossref PubMed Scopus (16) Google Scholar Besides targeting proinflammatory cascades, redox- and anesthetic-based approaches show promise to prevent chemotherapy-associated hemorrhagic cystitis. Two 2014 articles in the Indian Journal of Pharmacology address possible therapeutics for uroprotection against ifosfamide-induced hemorrhagic cystitis. The first publication examined the adjuvant use of reduced glutathione with mesna in ifosfamide-treated rodents. The authors concluded that glutathione has the potential to be at least as useful as mesna in patients being treated with ifosfamide.30Ali S. Danda S. Basha S.A. Rasheed A. Ahmed M. Ahmed O. Comparison of uroprotective activity of reduced glutathione with mesna in ifosfamide induced hemorrhagic cystitis in rats.Indian J Pharmacol. 2014; 46: 105https://doi.org/10.4103/0253-7613.125188Crossref PubMed Scopus (8) Google Scholar The second article studied the effects of a single dose of ketamine combined with mesna in ifosfamide-exposed rats. These investigations showed that ketamine combined with mesna reduced bladder wet weight, and that ketamine alone prevents microscopic changes associated with hemorrhagic cystitis.31Ozguven A. Taneli F. Ulman C. Vatansever S. Yilmaz O. Onag A. Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide.Indian J Pharmacol. 2014; 46: 147https://doi.org/10.4103/0253-7613.129301Crossref PubMed Scopus (12) Google Scholar Interestingly, ketamine abuse can itself lead to extensive cystitis.32Gray T. Dass M. Ketamine cystitis: an emerging diagnostic and therapeutic challenge.Br J Hosp Med (Lond). 2012; 73: 576-579http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=medl&NEWS=N&AN=23124288Crossref PubMed Scopus (14) Google Scholar Hence, focusing on preventing chemotherapy-induced hemorrhagic cystitis through use of ketamine and other potential drugs of abuse may be suboptimal. Alternative potential prophylactics for cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis may exist in the natural world. Specifically, Uncaria tomentosa is a naturopathic medicine derived from a plant in the Rubiaceae family and is used for urinary tract disease. U. tomentosa was studied by Dietrich et al in cyclophosphamide-induced hemorrhagic cystitis. They investigated quinovic acid glycosides purified fractions (QAPF) from U. tomentosa and its interaction with the P2X7 purine receptor, which is expressed in the bladder. The authors suggest that QAPF downregulates the P2X7 receptor, leading to decreased levels of IL-1β in the bladder. They also postulated that QAPF may complex with acrolein, thereby inactivating it. The authors concluded that this 2-pronged method of reducing the effects of cyclophosphamide on the bladder could lead to decreased incidence of cyclophosphamide-induced hemorrhagic cystitis.33Dietrich F. Martins J.P. Kaiser S. et al.The quinovic acid glycosides purified fraction from Uncaria tomentosa protects against hemorrhagic cystitis induced by cyclophosphamide in mice.PLoS ONE. 2015; 10: 1-16https://doi.org/10.1371/journal.pone.0131882Crossref Scopus (14) Google Scholar Dietrich et al's work suggests that products found in nature may have value as uroprotective agents for chemotherapy-induced hemorrhagic cystitis. Cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis remains a prevalent problem in the setting of treatment of a multitude of oncologic and rheumatologic conditions. Since the discovery of mesna and hyperhydration as uroprotective agents, investigators have sought to develop agents with superior efficacy and fewer side effects. Efforts targeting proinflammatory cascades and oxidation seem to have shown the most promise. However, no level 1 evidence has shown results superior to mesna for uroprotection against cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis. Clearly, additional research is needed to develop prophylactics against this devastating complication of chemotherapy.
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