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Home , Arsenic trioxide, Ifosfamide, Vincristine, Working Formulation

Correspondence Clinical activity of trioxide in Burkitt-like 271

Leukemia (2003) 17, 271–272. doi:10.1038/sj.leu.2402735

TO THE EDITOR Small non-cleaved cell (SNCL) as coined initially by Lukes and Collins and as used in the Working Formulation encompass Burk- itt’s lymphomas and non-Burkitt (Burkitt-like) lymphomas. The treat- ment of SNCLs involves combination consisting of intensive doses of alkylating agents (such as ) given together with other agents including , , and ara-C. With these regimens, overall survival rates of 80% to 90% have been reported.1,2 The cure rate for patients with mature B cell acute lymphoblastic , a closely related dis- order, is in the range of 40–60%.3 Patients withrecurrent disease have a poor prognosis. A small number of these patients respond to salvage regimens followed by high-dose chemotherapy and autologous or allogeneic stem cell transplantation. Therefore, exploration of agents withalternative and specific modes of action, for example by targeting the protein product of the c-myc proto-oncogene, may provide us withmore effective therapies.

Arsenic trioxide (As2O3) is a trivalent inorganic arsenical used as a medicinal agent particularly in Central and Southern Asia. Recent studies have established the role of As2O3 in the treatment of patients with relapsed acute promyelocytic leukemia. The exact mechanism of action of As2O3 in this setting is not clear and may be disease- specific. However, preclinical studies have suggested a broader anti- neoplastic activity including effects in myelodysplastic syndrome and Figure 1 Plot of level of lactate dehydrogenase against time. solid tumor cell lines. More recently, activity of As2O3 in lymphoid malignancies has been reported by a number of authors in in vitro studies.4,5 A synergistic effect between As O and ascorbic acid has 2 3 and was administered unsuccessfully7 withdem- been reported, suggesting a possible role for this combination in onstration of further progression of disease by imaging and a rapid patients withacute myeloid leukemia. We investigated theusefulness rise in LDH (Figure 1). Combination therapy with As O (0.25 mg/m2 of this combination in a patient with advanced, refractory Burkitt-like 2 3 intravenously over 2 hdaily), as well as ascorbic acid (500 mg orally non-Hodgkin’s lymphoma. twice daily) was commenced and was continued daily for a period The patient, a 29-year-old female, presented with night sweats, of 2 weeks. On day 10 of As O therapy, following an initial drop in weight loss of 30 lb over a 1-month period, back pain, and gastrointes- 2 3 serum LDH (Figure 1) and demonstration of disease stabilization by tinal symptoms withabdominal pain, nausea and vomiting. On clini- CT scan, 60 mg every 12 hfor five doses was administered cal examination she was found to have a large abdominal mass with in an attempt to improve the response. After a period of 1 week off clinically evident pleural effusions, but withno palpable peripheral therapy, a further five doses of As O were administered before dis- lymphadenopathy. Laboratory studies revealed an elevated LDH of 2 3 continuing treatment due to general debilitation. Side effects encoun- 419 ␮/l (normal range 90–180 ␮/l), beta-2-microglobulin of 2.4, nor- tered during therapy with As O included mild nausea, fatigue, sig- mal blood counts, and normal and renal function. On imaging 2 3 nificant edema of lower extremities, asymptomatic prolongation of QT studies she was noted to have marked lymphadenopathy involving the interval, and significant neutropenia requiring growthfactor support. upper aortic, celiac, juxtadiaphragmatic, internal mammary, anterior Following a 1-monthperiod of stabilization as demonstrated by CT mediastinal and paratracheal nodes. Marked thickening of the omen- scan and after the patient had received a total of 19 days of the combi- tum throughout the upper abdomen, as well as a large 9 × 12 cm nation, therapy was discontinued due to the side-effects, as well as mesenteric mass were demonstrated. Other findings included bilateral further disease progression. The patient did not receive any further pleural effusions and normal liver and spleen, as well as other intra- therapy and succumbed to her disease. abdominal structures. Biopsy of the omental mass revealed small to Significant progress in the therapy of SNCLs of Burkitt and Burkitt- medium-sized cells suggestive of non-cleaved B cell lymphoma. Flow like types has resulted in impressive response rates with current com- cytometry demonstrated a monoclonal B cell population withlambda bination regimens. Unfortunately, treatment options for patients with light chain restriction and positive staining for CD10, CD20, CD19, relapsed or refractory disease remains limited withonly occasional CD38 and IgM. The specimen was positive for the bcl-2 gene cures after allogeneic or autologous progenitor cell transplantation. rearrangement.6 A diagnosis of Burkitt-like lymphoma was estab- New agents withnovel mechanismsof action need to be explored in lished. Bone marrow examination as well as examination of cerebro- this setting, particularly in patients who are unable to undergo trans- spinal fluid was negative for involvement by lymphoma. Therapy with plantation. has demonstrated impressive activity in the hyperCVAD regimen3 was initiated and a repeat CT of abdomen patients with relapsed APL and has recently been approved for this after two cycles of treatment revealed a decrease in the size of the purpose. Preclinical studies have demonstrated activity of this agent omental mass. However, with recurrence of symptoms after the third in other malignancies including lymphoma.4,5 A preliminary report cycle of therapy, progression of the intra-abdominal disease was sus- from China also indicates activity of arsenic compounds in NHL,8 but pected and demonstrated by a repeat CT scan. A change of treatment suchactivity hasto our knowledge not been confirmed in a prospec- to the combination of CHOP and rituximab was unsuccessful with tive study in the West. We observed activity of this agent, in combi- further progression of disease and development of an ‘omental cake’, nation withascorbic acid and steroids, in a patient withrefractory as well as enlarging intra-abdominal nodes and new lung nodules. Burkitt-like lymphoma, as indicated by transient stabilization of radio- In preparation for an autologous stem cell transplant, therapy with logical findings and decrease in serum LDH. We propose further examination of this combination in patients with refractory aggressive lymphomas. This may allow possible roles for inclusion of the agent Correspondence: F Ravandi, The University of Illinois, Chicago, MC in earlier stages of the disease. 787, 840 SouthWood Street, Chicago,Illinois 60612-7323, USA; Fax: 312-413-4131 F Ravandi The University of Illinois, Chicago, IL Received 4 March2002; accepted 3 July 2002 K van Besien USA

Leukemia Correspondence 272 References and arrest by arsenic trioxide in lymphoid neoplasms. Leukemia 1998; 12: 1383–1391. 5 Zhu XH, Shen YL, Jing YK, Cai X, Jia PM, Huang Y, Tang W, Shi 1 MagrathI, Adde M, ShadA, Venzon D, Seibel N, Gootenberg J, GY, Sun YP, Dai J, Wang ZY, Chen SJ, Zhang TD, Waxman S, Neely J, Arndt C, Nieder M, Jaffe E, Wittes RA, Horak ID. Adults Chen Z, Chen GQ. and growth inhibition in malignant and children with small non-cleaved-cell lymphoma have a simi- lymphocytes after treatment with arsenic trioxide at clinically achi- lar excellent outcome when treated with the same chemotherapy evable concentrations. J Natl Inst 1999; 91: 772–778. regimen. J Clin Oncol 1996; 14: 925–934. 6 Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM, Bar- 2 Lee EJ, Petroni GR, Schiffer CA, Freter CE, Johnson JL, Barcos M, nett M, Gascoyne RD. Small noncleaved, non-Burkitt’s (Burkitt- Frizzera G, Bloomfield CD, Peterson BA. Brief-duration high- like) lymphoma: cytogenetics predict outcome and reflect clinical intensity chemotherapy for patients with small noncleaved-cell presentation. J Clin Oncol 1999; 17: 1558–1567. lymphoma or FAB L3 acute lymphocytic leukemia: results of Can- 7 van Besien K, Rodriguez A, Tomany S, Younes A, Donato M, Sarris cer and Leukemia Group B Study 9251. J Clin Oncol 2001; 19: A, Giralt S, Mehra R, Andersson B, Gajewski J, Champlin R, Cab- 4014–4022. anillas F. Phase II study of a high-dose ifosfamide-based chemo- 3 Kantarjian HM, O’Brien S, SmithTL, Cortes J, Giles FJ, Beran M, therapy regimen with growth factor rescue in recurrent aggressive Pierce S, HuhY, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy NHL. Highresponse rates and limited toxicity, but limited impact S, FreireichEJ. Results of treatment withhyper-CVAD,a dose- on long-term survival. Bone Marrow Transplant 2001; 27:397– intensive regimen, in adult acute lymphocytic leukemia. J Clin 404. Oncol 2000; 18: 547–561. 8 Li YS, Zhang TD, Li CW. Traditional Chinese and western medi- 4 Zhang W, Ohnishi K, Shigeno K, Fujisawa S, Naito K, Nakamura cine in the treatment of 27 patients with malignant lymphoma. S, Takeshita K, Takeshita A, Ohno R. The induction of apoptosis Zhonghua zhong liu za zhi (Chinese Journal of Oncology) 1988; 10: 61–62.

Zinc modulates c-Myc/Mad1 balance in human leukemia cells

Leukemia (2003) 17, 272–274. doi:10.1038/sj.leu.2402746

TO THE EDITOR (Zn++) is an essential component in the diet of mammals, and its deficiency has been associated with enhanced susceptibility to can- cer.1 Zn++ is found in more than 300 metalloenzymes, influencing gene expression by either structural stabilization or functional regu- lation of various transcription factors. However, the role of this metal ion in tumor development has not been yet elucidated. ␮ We report here that addition of 100 M ZnSO4 to cultures drasti- cally inhibited c-Myc protein expression in different types of human leukemia cells, and that its activity was concentration-dependent (Figures 1a and 2a). The inhibitory effect of Zn++ on c-myc expression was not related to a pro-apoptotic effect, since the percentage of apop- totic cells as assessed by AnnexinV-FITC cell binding did not change Ͻ in ZnSO4-treated cells, being 6% of total cells up to 24 hof treat- ment (data not shown). In contrast, the expression of either structurally or functionally related proteins Max and Tal-1 was not affected (Figure 2b and c). Interestingly, we observed that Zn++ reduced c-Myc protein levels also in Burkitt’s lymphoma cells (Raji cell line). In these cells, c-Myc expression is increased in basal conditions as a consequence of a deregulated rate of transcription, but this effect was not present in VLL lymphoblastoid B line, where c-Myc enhanced expression is mainly due to increased mRNA stability (Figure 2d).2 Further study is needed to clarify this issue. These findings were firstly observed using the Zn++ sulfate salt. To extend our results to other Zn++ salts, additional experiments were

performed using zinc acetate ((CH3COO)2Zn) and zinc chloride (ZnCl2). Both these zinc salts also elicited a significant inhibition of Figure 1 (a) Concentration-dependent inhibition of c-Myc c-myc expression (Figure 1b). To investigate the possible effect of expression by ZnSO4. HL-60 cells were incubated with0, 1, 10 or ␮ other metal ions on c-Myc expression and to exclude any possible 100 M ZnSO4. After 6 h, cells were collected and processed for direct activity of the sulfate, acetate or chloride ions, the effect of Western blot analysis. In (b) and (c), the activity of different metal salts different compounds including ferrous sulfate (FeSO ), acet- (sulfate, chloride and acetate) on c-Myc expression was compared (6 4 ␮ ate ((CH COO) Cd), as well as several metal chloride salts including h, 100 M). The effect of EDTA addition to ZnSO4 was also tested 3 2 ␮ CdCl2, FeCl3, HgCl2, SrCl2 and NiCl2 was also investigated. None of (b). In all experiments, 40 g of protein per lane were electrophoresed these substances was found to inhibit c-Myc expression (Figure 1c on 8% SDS-polyacrylamide gel and then transferred on to hybond- and d). C membranes. In experiment (b), ␤-actin expression for eachlane is also shown.

Correspondence: M Paroli, Dipartimento di Medicina Interna, Poli- c-Myc is a transcription factor that plays a pivotal role in the regu- clinico Umberto I, V.le del Policlinico, 155, Roma, 00161, Italy; Fax: lation of cell growth, cell-cycle progression, apoptosis and terminal +39-06-4940594 differentiation.3 Therefore, perturbation of c-Myc levels is critical in Received 12 December 2001; accepted 29 July 2002 influencing growthof malignant cells, and in particular in thoseof

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