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Yuji Ishimatsu, MD, PhD; Hiroshi Mukae, MD, PhD; Noriho Sakamoto, MD, PhD
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From the Second Department of Internal Medicine (Drs Ishimatsu, Mukae, and Sakamoto), Nagasaki University School of Medicine; and the Division of Respiratory Medicine (Dr Mukae), University of Occupational and Environmental Health, Kitakyushu, Japan.

Correspondence to: Hiroshi Mukae, MD, PhD, Division of Respiratory Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan 807-8555; e-mail: hmukae@med.uoeh-u.ac.jp


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(3):725-726. doi:10.1378/chest.10-2768
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To the Editor:

Dr Ferreri’s letter notes the efficacy of clarithromycin as an antiproliferative drug in the treatment of mucosa-associated lymphoid tissue (MALT)-type lymphoma based on their phase 2 trial of patients who received clarithromycin for 6 months following various pretreatments, including doxycyclin1 and our report of two patients with pulmonary MALT lymphoma successfully treated with clarithromycin without control of the underlying chronic infectious diseases.2 We are also interested in the direct antineoplastic effect of clarithromycin on MALT lymphoma in addition to the antimicrobial effect described by Ferreri.

We should not overlook the fact that reports of MALT lymphoma successfully treated with clarithromycin only cover a few organs, such as the ocular adnexae and lungs, as Govi et al1 and we have reported.2 Therefore, we agree with Ferreri that the involvement of undetected microorganisms sensitive to clarithromycin cannot be excluded in cases in which MALT lymphoma is improved by clarithromycin.

However, we anticipate a direct antineoplastic effect of clarithromycin on two grounds. First, the pathogenesis of MALT lymphoma may be associated with the inhibition of apoptosis via nuclear factor (NF) activation and B-cell lymphoma-extra large (Bcl-xL) expression: MALT lymphoma typically originates from chronic inflammation (eg, from Helicobacter pylori gastritis in the stomach or Sjögren syndrome in the salivary glands), which has been reported to cause antiapoptosis via NF-κB activation.3 On the other hand, several genetic aberrations have been identified in MALT lymphomas, one of which is apoptotic inhibitor 2-MALT1 chimeric gene, which encodes the protein that plays a role in NF-κB activation and correlates well with resistance to H pylori-eradication treatment of gastric MALT lymphoma. Furthermore, in vivo overexpression of Bcl-xL protein, which is reported to be induced by NF-κB and is associated with inhibition of apoptosis, was observed in gastric MALT lymphoma-like lesions in H pylori-infected mice.4 Second, clarithromycin may affect apoptosis and NF-κB activation: clarithromycin was reported to suppress Bcl-xL expression, resulting in apoptosis directly in human-activated lymphocytes,5 and to inhibit NF-κB activation in human peripheral blood mononuclear cells.6

In summary, we speculate that clarithromycin might directly regulate the suppressed apoptosis in MALT lymphoma caused by chronic inflammation even if that inflammation is uncontrolled and that it might have a direct antineoplastic effect on MALT lymphoma. Further investigations are needed to clarify whether there is antineoplastic activity in clarithromycin.

Govi S, Dognini GP, Licata G, et al. Six-month oral clarithromycin regimen is safe and active in extranodal marginal zone B-cell lymphomas: final results of a single-centre phase II trial. Br J Haematol. 2010;1502:226-229. [PubMed]
 
Ishimatsu Y, Mukae H, Matsumoto K, et al. Two cases with pulmonary mucosa-associated lymphoid tissue lymphoma successfully treated with clarithromycin. Chest. 2010;1383:730-733. [CrossRef] [PubMed]
 
Seto M. Genetic and epigenetic factors involved in B-cell lymphomagenesis. Cancer Sci. 2004;959:704-710. [CrossRef] [PubMed]
 
Fukui T, Okazaki K, Tamaki H, et al. Immunogenetic analysis of gastric MALT lymphoma-like lesions induced byHelicobacter pyloriinfection in neonatally thymectomized mice. Lab Invest. 2004;844:485-492. [CrossRef] [PubMed]
 
Mizunoe S, Kadota J, Tokimatsu I, Kishi K, Nagai H, Nasu M. Clarithromycin and azithromycin induce apoptosis of activated lymphocytes via down-regulation of Bcl-xL. Int Immunopharmacol. 2004;49:1201-1207. [CrossRef] [PubMed]
 
Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother. 2001;451:44-47. [CrossRef] [PubMed]
 

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References

Govi S, Dognini GP, Licata G, et al. Six-month oral clarithromycin regimen is safe and active in extranodal marginal zone B-cell lymphomas: final results of a single-centre phase II trial. Br J Haematol. 2010;1502:226-229. [PubMed]
 
Ishimatsu Y, Mukae H, Matsumoto K, et al. Two cases with pulmonary mucosa-associated lymphoid tissue lymphoma successfully treated with clarithromycin. Chest. 2010;1383:730-733. [CrossRef] [PubMed]
 
Seto M. Genetic and epigenetic factors involved in B-cell lymphomagenesis. Cancer Sci. 2004;959:704-710. [CrossRef] [PubMed]
 
Fukui T, Okazaki K, Tamaki H, et al. Immunogenetic analysis of gastric MALT lymphoma-like lesions induced byHelicobacter pyloriinfection in neonatally thymectomized mice. Lab Invest. 2004;844:485-492. [CrossRef] [PubMed]
 
Mizunoe S, Kadota J, Tokimatsu I, Kishi K, Nagai H, Nasu M. Clarithromycin and azithromycin induce apoptosis of activated lymphocytes via down-regulation of Bcl-xL. Int Immunopharmacol. 2004;49:1201-1207. [CrossRef] [PubMed]
 
Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother. 2001;451:44-47. [CrossRef] [PubMed]
 
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