Anti-Cachectic Effect of Clarithromycin for Patients with Unresectable Non-Small Cell Lung Cancer

Abstract

We have previously reported that long-term treatment with clarithromycin (CAM) increased the median survival of patients with non-small cell lung cancer, and improved various clinical parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer, who had received chemotherapy, radiotherapy or both (basic cancer therapy). Patients with clinical backgrounds matched to the CAM group, who did not receive CAM treatment, were included into this study as a control group (non-CAM group). CAM treatment was initiated 4 weeks after the basic cancer therapy. The non-CAM group did not receive a placebo. Before and after the 3-month treatment with CAM, body weight, serum levels of interleukin-6 (IL-6, a cytokine which, together with TNF-α, plays a crucial role in the development of cancer cachexia), total protein, albumin, cholinesterase and hemoglobin were measured for the evaluation of the patients’ clinical status. There were no statistically significant differences in serum levels of IL-6 between the CAM group before the treatment and the non-CAM group. After 3 months of CAM treatment, serum levels of IL-6 significantly decreased. In contrast, body weight, cholinesterase, and hemoglobin increased to a significant extent. Among these four parameters, however, the decrease in serum IL-6 levels was only statistically correlated with the increase in body weight, but not with that in other parameters. Furthermore, CAM-treated patients whose serum IL-6 levels were decreased after 3 months of treatment survived longer: there was a statistically significant correlation between the decrease in serum IL-6 and survival time. In contrast, in the non-CAM group, these parameters did not change significantly during the study. These results suggest that CAM may reduce the progression of cancer-associated cachexia.

Adjuvant Effect of Clarithromycin on Chemotherapy for Murine Lung Cancer

“…Such an effect was explained in part by the ability of CAM to enhance IL-12 production by peripheral blood mononuclear cells [12], as well as to suppress the production of cachexiarelated cytokines, including IL-6 and tumor necrosis factor · [13,14]. However, the optimal dosage and timing of CAM treatment as a supportive drug for chemotherapy in patients with lung cancer remains unclear.…”

Is clarithromycin a potential treatment for cachexia in people with lung cancer? A feasibility study

“…In proposing its long-term use as a cachexia treatment, we consider additional caution appropriate, particularly given concerns about prolongation of the QT interval and the increased risk of ventricular arrhythmias and sudden cardiac death observed in patients receiving CLM (and other macrolides) [16]. Previous studies of CLM for cancer cachexia predate the emergence of these safety concerns [7,8].…”

“…Given the preliminary reports of impressive benefits of CLM in cancer cachexia [7,8], rather than abandon this area completely, the potential exists to explore the feasibility of using alternate macrolide antimicrobials. For example, although azithromycin has no 'track record' in cachexia, it also has immunomodulatory properties [17,18], is used long-term [19,20], and has a lower risk of a drug-drug interaction, such that only 10 of our patients would have been excluded on this basis.…”

“…No standard treatment exists and cachexia is a major unmet need [5,6]. Clarithromycin (CLM) is reported to preserve body weight, physical independence and increase survival in patients with lung cancer [7,8]. The mechanism may relate to its anti-inflammatory effect as inflammation appears a key contributor to cachexia [9][10][11].…”

Amplification of Lipopolysaccharide-Induced Cytokine Synthesis in Non–Small Cell Lung Cancer/Neutrophil Cocultures

“…In pilot experiments, assessing IL-8 and IL-6 mRNA after various time points (1,4,8, and 24 h), expression of cytokine mRNA plateaued after 8 h in both cell types, therefore, this incubation period was selected for further experiments. After an incubation period of 8 h, the neutrophil-containing supernatants were harvested and washed twice at 300 × g, whereas the A549 monolayer was washed twice, cells were digested with trypsin, washed again, and pelleted.…”