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Antitumor Activity of Nifurtimox Observed In a Patient Giselle L. Saulnier Sholler, MD,*w z Satyan Kalkunte, MSc,y Carla Greenlaw, MD,*w Kathleen McCarten, MD,*J and Edwin Forman, MD*w unexpected response to combination treatment with Background: Chemotherapy-resistant neuroblastoma is a diffi- cytoxan, topotecan, and nifurtimox. Nifurtimox is a cult disease to treat with poor survival.
nitroheterocyclic compound used in the treatment of Observations: We treated a patient with neuroblastoma who had Chagas disease.3 It’s mechanism of action involves the progressed on conventional chemotherapy. This 5-year-old girl formation of free radicals and redox cycling ultimately with chemotherapy-resistant neuroblastoma developed Chagas damaging functionally important biomolecules resulting disease at the start of salvage chemotherapy for which she was in cell death. This led us to hypothesize that nifurtimox also started on nifurtimox. The neuroblastoma response to these may have been effective in treating the neuroblastoma.
treatments resulted in clinical remission. In vitro, treatment of aneuroblastoma cell line with nifurtimox resulted in decreased cell viability whereas no effect was seen on an endothelial cellline.
Conclusions: Nifurtimox shows promise as a potential new A 5-year-old girl presented with an abdominal mass.
Biopsy of the mass revealed a neuroblastoma with MYCN treatment for neuroblastoma and warrants further testing.
amplification and unfavorable histology. Her staging workup Key Words: neuroblastoma, nifurtimox, treatment showed a primary tumor arising from the right adrenal, with metastases to her abdominal lymph nodes, bone and bone (J Pediatr Hematol Oncol 2006;00:000–000) marrow. She was treated with 5 cycles of chemotherapy, whichincluded cisplatin, etoposide, vincristine, adriamycin, cyclopho- sphamide, iphosphamide, and carboplatin. She subsequently Neuroblastoma is the most common extracranial solid underwent debulking surgery where it was noted that she had a 81 tumor in children with approximately 700 new cases large adrenal tumor and extensive neuroblastoma studding ofher omentum and liver. Her bone marrow was free of each year in the United States. It is a disease that varies neuroblastoma cells but her bone metastases continued to be significantly in its clinical course. In children less than 1 present on MIBG scan. Owing to progressive disease, it was AQ3 year of age it usually presents with stage I/II disease and decided that she would not receive myeloablative consolidation may spontaneously regress. Overall survival at this age is and was started on salvage chemotherapy with cyclopho- 95%. In children over 1 year of age with advanced-stage sphamide and topotecan. At this time, the presence of a parasite disease, it is extremely aggressive with only a 30% was noticed on a peripheral blood smear and the patient was survival despite intensive treatment.1,2 Furthermore, diagnosed with Chagas disease. It was found that she had patients with neuroblastoma unresponsive to chemother- acquired Chagas disease from a blood transfusion during her apy tend to progress rapidly with high mortality. Well- treatment and she was started on nifurtimox. The infected blood tolerated new treatments are needed for these patients.
donor was subsequently identified. While receiving nifurtimox incombination with cyclophosphamide and topotecan, she de- Here we report the case of a patient with monstrated a good response with regression of her neuroblas- chemotherapy-resistant neuroblastoma who shows an toma and she went into remission assessed by computed tomography (CT) scan (Fig. 1) as well as a negative bone marrow and MIBG scan. She had a few episodes of severe neutropenia and fever, one of which resulted in life-threatening Received for publication March 14, 2006; accepted August 20, 2006.
From the *Hasbro Children’s Hospital, Lifespan; Departments of sepsis. Thus, the toxicity of cyclophosphamide and topotecan wPediatrics; JRadiology, Brown University, Providence, RI; led us to pursue decreases in dosages and increases in intervals.
zDepartment of Pediatrics, University of Vermont College of During these last months, we utilized quite minimal and Medicine, Burlington, VT; and yProgram in Women’s Oncology, infrequent, and thus possibly ineffective, doses of these Department of Obstetrics and Gynecology, Women and Infants’ chemotherapies. After 1 year of treatment, the chemotherapy was stopped. She remained on nifurtimox for 3 months, on the Supported by Training Grant from the Department of Pediatrics, basis of recommendations from infectious disease due to her Division of Hematology/Oncology to Dr Saulnier Sholler immunocompromised state. Two months after the discontinua- Reprints: Giselle Saulnier Sholler, MD, Departments of Pediatrics, tion of nifurtimox, an enlarging axillary lymph node and her University of Vermont College of Medicine, 111 Colchester Avenue,Burlington VT 05401 (e-mail: [email protected]).
bone marrow demonstrated neuroblastoma recurrence. The Copyright r 2006 by Lippincott Williams & Wilkins axillary lymph node was resected and the patient was restarted J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2006 J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2006 was a large retroperitoneal mass withcalcification encircling the aorta, displa- cing other major vessels, and obstructingthe right kidney. B, Postoperatively, multi- ple clips are seen in the surgical bed. C,The surgical clips are more closely apposed to one another indicating reduction inresidual disease. D, Stable disease (MIBG on cyclophosphamide, topotecan and nifurtimox (to prevent the 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- reactivation of Chagas disease). After 6 weeks of this treatment, tetrazolium]5 was added to each well in fresh media to a her CT scan and bone marrow were negative. Owing to multiple final concentration of 0.5 mg/ml and incubated for 4 relapses she was then placed on phase 1 studies.
hours. Absorbance was measured at 490 nm using a microplate reader (Multiskan RC, Fisher Scientific Pittsburgh, PA). Cell viability is represented as the mean At diagnosis, a CT scan of the abdomen showed a large percentage ± SD of absorbance before and after treat- infiltrating tumor in the retroperitoneum encasing many of the major vessels (Fig. 1A). After standard therapy described above, the patient was found to still have significant tumor volume. Sheunderwent debulking surgery (Fig. 1B) and was started on cyclophosphamide and topotecan. After only 4 weeks of nifurtimox, cyclophosphamide, and topotecan, the tumor Nifurtimox Suppresses the Cell Viability of showed a response (Fig. 1C) that resulted in remission after 6 months (Fig. 1D). Her MIBG scan and bone marrow at this The growth inhibitory effect of nifurtimox on SMSKCNR neuroblastoma cell line and HMVEC endothelial cell lines were determined by MTS assay. As shown in Figure 2, nifurtimox inhibited the growth of the The dramatic response of her chemotherapy-resistant, neuroblastoma cell lines significantly in a dose-dependent multiply-relapsed, neuroblastoma to treatment with salvage manner but showed no decrease in the cell viability of the chemotherapy with nifurtimox led us to further study the endothelial cells. The cell viability was decreased to 37% specificity and sensitivity of nifurtimox on neuroblastoma cells.
(SMSKCNR) after 120 hours of treatment at 20 mg/ml We used an established aggressive MYCN amplified neuroblas-toma cell line (SMSKCNR) and a control endothelial cell line nifurtimox. IC50 value, the concentration required to (HMVEC) to examine the effect of nifurtimox on cell viability.
reach 50% inhibition of growth, for this cell line wasdetermined to be 14.7 mg/ml. These studies clearly show that nifurtimox is specifically cytotoxic to this neuroblas- Cell viability was measured using the CellTiter 96 AQ One Solution Cell Proliferation Assay kit (Promega, Childhood neuroblastoma is a very aggressive Madison WI).4 Cells were cultured (50,000 per well) in 48- disease and a leading cause of cancer deaths among well plates for 24 hours and treated with increasing children. Children with relapsed disease rarely respond to concentrations of nifurtimox (0, 1, 5, 10, and 20 mg/ml) further treatments. In the case described here, we for either 48 or 96 hours. Vehicle treated cells were used observed an unexpected clinical response in a patient as control (0.001% dimethylsulfoxide). At the end of the receiving chemotherapy in conjunction with nifurtimox incubation period, MTS reagent [3-(4,5-dimethylthiazol- after progression of disease and again at relapse. It is not J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2006 Effect of Nifurtimox on SMS KCNR cells after 96h
due to the reaction of nifurtimox with catecholamine treatment
neurotransmitters. This reduction reaction results in the formation of nitro anion radicals and semiquinone radicals.8 This may play a role in the sensitivity of neuroblastoma cells because these cells also contain catecholamines such as dopamine within the cells.
Cell Viability
(% Control)
The IC50 of nifurtimox on this neuroblastoma cell line, SMSKCNR, was 14.7 mg/ml. Serum concentrations of nifurtimox after a single dose of 15 mg/ml in adults Nifurtimox Concentration (ug/ml)
peaked at 3 mg/ml.9 This dose is used in the treatment of Chagas disease. It remains to be determined whether Effect of Nifurtimox on cytotoxicity HMVEC and
higher levels may be achievable in children treated for SMSKCNR cells after 48h treatment
neuroblastoma or whether this dose of nifurtimox may be Disseminated neuroblastoma in children over 1 year of age is a very difficult disease to treat. Current Cell Viability
(% Control)
treatments of intensive chemotherapy, surgery, radiation, and autologous bone marrow transplant are often Nifurtimox Concentration (ug/ml)
unsuccessful, leaving the patients weak and unable to FIGURE 2. A, SMSKCNR neuroblastoma cells were cultured in tolerate more intense treatment. Therefore, well-tolerated 48-well plates and treated with 1–20 mg/ml nifurtimox for 96 new treatments are needed. In treating a neuroblastoma hours. Cell viability was assessed with MTS assay as described cell line with nifurtimox, we observed a specific decrease in the Methods and expressed as a percentage of vehicle in neuroblastoma cell viability. Conversely, nifurtimox control. B, SMSKCNR neuroblastoma cells and HMVEC did not decrease the cell viability of endothelial cells. This endothelial cells were cultured in 48-well plates and treated case and preliminary studies indicate that nifurtimox may with 10 or 20 mg/ml nifurtimox for 48 hours. Cell viability wasassessed with MTS assay as described in the Methods and be effective against neuroblastoma. Further study of expressed as a percentage of vehicle control.
nifurtimox is warranted to develop this drug as apotential new treatment for neuroblastoma.
known whether it was the chemotherapy or the nifurti- mox that resulted in tumor response. This raised the possibility of nifurtimox playing a role and led us to 1. Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the further investigate the sensitivity and specificity of international criteria for neuroblastoma diagnosis, staging, and nifurtimox treatment on a neuroblastoma cell line.
response to treatment. J Clin Oncol. 1993;11:1466–1477.
2. Brodeur GM, Maris JM, Yamashiro DJ, et al. Biology and genetics The mechanism of action of nifurtimox involves the of human neuroblastomas. J Pediatr Hematol Oncol. 1997;19:93–101.
generation of free radicals, which causes cell death in 3. Coura JR, de Castro SL. A critical review on Chagas disease Trypanosoma cruzi.3 The side effects of nifurtimox include chemotherapy. Mem Inst Oswaldo Cruz. 2002;97:3–24.
anorexia with weight loss, nausea, vomiting, dermatitis, 4. Raether W, Hanel H. Nitroheterocyclic drugs with broad spectrum leukopenia, hepatotoxicity, and central nervous system activity. Parasit Res. 2003;90:S19–S39.
5. Malich G, Markovic B, Winder C. The sensitivity and specificity of (CNS) effects. The effects on the CNS include sleep the MTS tetrazolium assay for detecting the in vitro cytotoxicity of 20 disorders, headache, weakness, fatigue, paresthesias or chemicals using human cell lines. Toxicology. 1997;124:179–192.
peripheral neuropathy, CNS excitation, vertigo, ataxia, 6. Wegner DHG, Rohwedder RW. The effect of nifurtimox in acute tremors, and memory impairment.6,7 These side effects Chagas’ infection. Arzneim Forsch. 1972;22:1624–1635.
7. VanVoorhis WC. Therapy and prophylaxis of systemic protozoan are better tolerated in children than in adults. Our patient infections. Drugs. 1990b;40:176–202.
tolerated this medication extremely well. She had only 8. Ramakrishna Rao DN, Mason RP. Generation of nitro radical mild anorexia, without nausea or vomiting, which could anions of some 5-nitrofurans, 2-and 5-nitroimidazoles by norepi- have well been due to the cyclophosphamide and/or topotecan treatments. It is interesting to note the 9. Medenwald H, Brandau K, Schlossmann K. Quantitative determina- significant side effects on neuronal cells. The neurotoxi- tion of nifurtimox in body fluids of rat, dog and man. Arzneim Forsch city associated with nifurtimox is reported to possibly be Author(s) Name____________________________________________________________ 2005/2006 Author Reprint Rates
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