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Activity of Clarithromycin in Mucosa-Associated Lymphoid Tissue-Type Lymphomas: Antiproliferative Drug or Simple Antibiotic? FREE TO VIEW

Andrés J. M. Ferreri, MD
Author and Funding Information

From the Unit of Lymphoid Malignancies, Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute.

Correspondence to: Andrés J. M. Ferreri, MD, Unit of Lymphoid Malignancies, Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy; e-mail: andres.ferreri@hsr.it


Financial/nonfinancial disclosures: The author has 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):724-725. doi:10.1378/chest.10-2454
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Published online

To the Editor:

The report in CHEST (September 2010) by Ishimatsu et al1 of two cases of pulmonary mucosa-associated lymphoid tissue (MALT)-type lymphoma successfully treated with clarithromycin is in line with our recently reported phase 2 trial.2 Our trial showed that a 6-month regimen of oral clarithromycin (500 mg bid) is feasible and active in heavily pretreated patients with MALT-type lymphoma arising in different organs, with an objective response rate of 38%, mostly in lymphomas occurring in the ocular adnexae. In our series, there were no cases of pulmonary MALT lymphoma, and cases reported by Ishimatsu and colleagues1 expand the spectrum of MALT lymphomas sensitive to this macrolide.

It is important to understand the mechanism of action of clarithromycin in these lymphomas. Even if the list of MALT lymphomas associated with infectious agents is growing, both of our studies seem to suggest that clarithromycin activity resulted from a direct antiproliferative effect instead of an antimicrobial-mediated consequence. In fact, sinubronchial syndrome persisted after clarithromycin in the first patient treated by Ishimatsu and colleagues,1 and Helicobacter pylori eradication was ineffective in the second one. In our series, all infections from H pylori or Chlamydophila psittaci were successfully eradicated years before trial enrollment.2 The role of macrolides as potential antineoplastic and immunomodulatory agents is supported by three levels of evidence. First, in vitro studies have shown the capability of these antibiotics to induce antitumor activity of macrophages, natural killer cells, and CD8 cytotoxic T cells3; to reduce neutrophil production of IL-84; to inhibit tumor necrosis factor (TNF)-α and vascular endothelial growth factor activity3; to enhance intracellular cytostatic concentrations5; to suppress the production of TNF-α and IL-6 in adenocarcinoma cells6; to induce apoptosis in lymphoid tumor cells7; and to be substrates of P-glycoprotein,8 a molecule strongly linked to anticancer drug resistance. Second, in vivo studies have shown that oral clarithromycin is associated with encouraging results in murine models of lung cancer and potentiate cytostatics in mice inoculated with melanoma cells.6 Third, the use of clarithromycin, alone or in combination with other immunomodulatory agents (lenalidomide, dexamethasone), was associated with encouraging results in trials on multiple myeloma and Waldenström macroglobulinemia9 and in anecdotal cases of relapsed Hodgkin’s lymphoma10 and gastrointestinal MALT lymphoma.11

Despite this amount of evidence in favor of a direct antitumor activity of clarithromycin and other macrolides, the involvement of undetected microorganisms sensitive to these antibiotics cannot be excluded in our studies, and it is important to underline that several bacteria cause chronic infections by persistent, inactive (quiescent) forms that are unresponsive to antibiotics but that can respond in the case of prolonged treatment like that performed in our studies. Thus, additional experience with clarithromycin treatment, with adequate biologic investigations, is needed to explore its antineoplastic mechanisms.

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]
 
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]
 
Aoki D, Ueno S, Kubo F, et al. Roxithromycin inhibits angiogenesis of human hepatoma cells in vivo by suppressing VEGF production. Anticancer Res. 2005;251A:133-138. [PubMed]
 
Kurdowska A, Noble JM, Griffith DE. The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages. J Antimicrob Chemother. 2001;476:867-870. [CrossRef] [PubMed]
 
Wang L, Kitaichi K, Hui CS, et al. Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo. Clin Exp Pharmacol Physiol. 2000;278:587-593. [CrossRef] [PubMed]
 
Hamada K, Mikasa K, Yunou Y, et al. Adjuvant effect of clarithromycin on chemotherapy for murine lung cancer. Chemotherapy. 2000;461:49-61. [CrossRef] [PubMed]
 
Ohara T, Morishita T, Suzuki H, Masaoka T, Ishii H, Hibi T. Antibiotics directly induce apoptosis in B cell lymphoma cells derived from BALB/c mice. Anticancer Res. 2004;246:3723-3730. [PubMed]
 
Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther. 1998;641:123-128. [CrossRef] [PubMed]
 
Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;1113:1101-1109. [CrossRef] [PubMed]
 
Sauter C, Blum S. Regression of lung lesions in Hodgkin’s disease by antibiotics: case report and hypothesis on the etiology of Hodgkin’s disease. Am J Clin Oncol. 2003;261:92-94. [CrossRef] [PubMed]
 
Arima N, Tsudo M. Extragastric mucosa-associated lymphoid tissue lymphoma showing the regression byHelicobacter pylorieradication therapy. Br J Haematol. 2003;1205:790-792. [CrossRef] [PubMed]
 

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References

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]
 
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]
 
Aoki D, Ueno S, Kubo F, et al. Roxithromycin inhibits angiogenesis of human hepatoma cells in vivo by suppressing VEGF production. Anticancer Res. 2005;251A:133-138. [PubMed]
 
Kurdowska A, Noble JM, Griffith DE. The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages. J Antimicrob Chemother. 2001;476:867-870. [CrossRef] [PubMed]
 
Wang L, Kitaichi K, Hui CS, et al. Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo. Clin Exp Pharmacol Physiol. 2000;278:587-593. [CrossRef] [PubMed]
 
Hamada K, Mikasa K, Yunou Y, et al. Adjuvant effect of clarithromycin on chemotherapy for murine lung cancer. Chemotherapy. 2000;461:49-61. [CrossRef] [PubMed]
 
Ohara T, Morishita T, Suzuki H, Masaoka T, Ishii H, Hibi T. Antibiotics directly induce apoptosis in B cell lymphoma cells derived from BALB/c mice. Anticancer Res. 2004;246:3723-3730. [PubMed]
 
Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther. 1998;641:123-128. [CrossRef] [PubMed]
 
Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;1113:1101-1109. [CrossRef] [PubMed]
 
Sauter C, Blum S. Regression of lung lesions in Hodgkin’s disease by antibiotics: case report and hypothesis on the etiology of Hodgkin’s disease. Am J Clin Oncol. 2003;261:92-94. [CrossRef] [PubMed]
 
Arima N, Tsudo M. Extragastric mucosa-associated lymphoid tissue lymphoma showing the regression byHelicobacter pylorieradication therapy. Br J Haematol. 2003;1205:790-792. [CrossRef] [PubMed]
 
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