zithromax and Neoplasms

Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.

Topics: Azithromycin; Hematopoietic Stem Cell Transplantation; Humans; Metabolic Networks and Pathways; Neoplasms; Stem Cell Transplantation

Autophagy plays an important role in tumour cell growth and survival and also promotes resistance to chemotherapy. Hence, autophagy has been targeted for cancer therapy. We previously reported that macrolide antibiotics including azithromycin (AZM) inhibit autophagy in various types of cancer cells in vitro. However, the underlying molecular mechanism for autophagy inhibition remains unclear. Here, we aimed to identify the molecular target of AZM for inhibiting autophagy.. We identified the AZM-binding proteins using AZM-conjugated magnetic nanobeads for high-throughput affinity purification. Autophagy inhibitory mechanism of AZM was analysed by confocal microscopic and transmission electron microscopic observation. The anti-tumour effect with autophagy inhibition by oral AZM administration was assessed in the xenografted mice model.. We elucidated that keratin-18 (KRT18) and α/β-tubulin specifically bind to AZM. Treatment of the cells with AZM disrupts intracellular KRT18 dynamics, and KRT18 knockdown resulted in autophagy inhibition. Additionally, AZM treatment suppresses intracellular lysosomal trafficking along the microtubules for blocking autophagic flux. Oral AZM administration suppressed tumour growth while inhibiting autophagy in tumour tissue.. As drug-repurposing, our results indicate that AZM is a potent autophagy inhibitor for cancer treatment, which acts by directly interacting with cytoskeletal proteins and perturbing their dynamics.

Topics: Animals; Anti-Bacterial Agents; Autophagy; Azithromycin; Cytoskeletal Proteins; Disease Models, Animal; Macrolides; Mice; Neoplasms

Cancer patients are prescribed antibiotics, such as macrolides and lactamides, for infection treatment. However, the effect of these antibiotics on NLRP3 activation remains largely unknown.. Lung cancer (A549) and prostate cancer (PC3) cell lines were primed with lipopolysaccharide (LPS) to activate NLRP3 transcription. Cells were then treated with azithromycin (Az) or ceftriaxone (Cf). NLRP3 activation was analyzed by qPCR, Western blot, and ELISA. Cell growth and viability were assessed by real-time cell analysis and Annexin V expression. Levels of 41 cytokines were also analyzed using a multiplex assay.. LPS-Az activated transcription of. Our data suggest that Cf could suppress LPS induced NLRP3, which should be considered when selecting antibiotics for cancer treatment. In contrast, the effect of Az on LPS primed NLRP3 and the inflammatory cytokines production appears to depend on the cancer cell origin. Therefore, these data indicate that considerations are required when selecting Az for the treatment of cancer patients.

Topics: Azithromycin; Ceftriaxone; Cell Line, Tumor; Cytokines; Humans; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Neoplasms; NLR Family, Pyrin Domain-Containing 3 Protein

Topics: Adolescent; Adrenal Cortex Hormones; Antiviral Agents; Azithromycin; Child; Child, Preschool; COVID-19; COVID-19 Drug Treatment; Female; Humans; Infant; Ivermectin; Male; Neoplasms; Palliative Care; Peru; SARS-CoV-2; Treatment Outcome

We aimed to investigate the factors affecting the mortality of patients aged 65 years or older who were hospitalized with the diagnosis of new coronavirus pneumonia (COVID-19).. This is a retrospective study of patients 65 years old or older with COVID-19 who were hospitalized in İstanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty Hospital, between March 11 and May 28, 2020. Demographic, clinical, treatment, and laboratory data were extracted from electronic medical records. We used univariate and multivariate logistic regression methods to explore the risk factors for in-hospital death.. A total of 218 patients (112 men, 106 women) were included, of whom 166 were discharged and 52 died in hospital. With univariate analysis, various clinical features and laboratory variables were found to be significantly different (i.e. P < 0.05). In multivariate logistic regression analysis the following were independently associated with mortality: present malignancy [odds ratio (OR) = 4.817, 95% confidence interval (CI) = 1.107–20.958, P: 0.036]; dyspnea (OR = 4.652, 95% CI = 1.473–14.688, P: 0.009); neutrophil/lymphocyte ratio (NLR; OR = 1.097, 95% CI = 1.012–1.188, P: 0.025); the highest values of C-reactive protein (CRP; OR = 1.006, 95% CI = 1.000–1.012, P: 0.049), lactate dehydrogenase (LDH; OR = 1.002, 95% CI = 1.001–1.004, P: 0.003), and creatinine levels (OR = 1.497, 95% CI = 1.126–1.990, P: 0.006); oxygen saturation (SpO2) values on admission (OR = 0.897, 95% CI = 0.811–0.993, P: 0.036); and azithromycin use (OR = 0.239, 95% CI = 0.065–0.874, P: 0.031).. The presence of malignancy; symptoms of dyspnea; high NLR; highest CRP, LDH, and creatinine levels; and low SpO2 on admission predicted mortality. On the other hand, azithromycin use was found to be protective against mortality. Knowing the causes predicting mortality will be important to treat future cases more successfully.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; C-Reactive Protein; Comorbidity; Coronary Artery Disease; COVID-19; Creatinine; Diabetes Mellitus, Type 2; Dyspnea; Female; Heart Failure; Humans; Hypertension; Hypoxia; L-Lactate Dehydrogenase; Leukocyte Count; Lymphocyte Count; Male; Neoplasms; Neutrophils; Prognosis; Pulmonary Disease, Chronic Obstructive; Risk Factors; SARS-CoV-2; Severity of Illness Index; Turkey

Recent advances in machine learning promise to yield novel insights by interrogation of large datasets ranging from gene expression and mutation data to CRISPR knockouts and drug screens. We combined existing and new algorithms with available experimental data to identify potentially clinically relevant relationships to provide a proof of principle for the promise of machine learning in oncological drug discovery. Specifically, we screened cell line data from the Cancer Dependency Map for the effects of azithromycin, which has been shown to kill cancer cells in vitro. Our findings demonstrate a strong relationship between Kallikrein Related Peptidase 6 (KLK6) mutation status and the ability of azithromycin to kill cancer cells in vitro. While the application of azithromycin showed no meaningful average effect in KLK6 wild-type cell lines, statistically significant enhancements of cell death are seen in multiple independent KLK6-mutated cancer cell lines. These findings suggest a potentially valuable clinical strategy in patients with KLK6-mutated malignancies.

Topics: Anti-Bacterial Agents; Azithromycin; Databases, Genetic; Databases, Pharmaceutical; Drug Discovery; Humans; Kallikreins; Machine Learning; Mutation; Neoplasms

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

Topics: Azithromycin; Bronchiolitis Obliterans; Hematopoietic Stem Cell Transplantation; Humans; Lung Transplantation; Neoplasms; Retrospective Studies; Transplantation, Homologous

Topics: Age Factors; Aged; Aged, 80 and over; Antiviral Agents; Azithromycin; Betacoronavirus; Ceftriaxone; Cobicistat; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Darunavir; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Hydroxychloroquine; Italy; Lopinavir; Male; Methylprednisolone; Middle Aged; Neoplasms; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2

There are no large reported series determining the Covid-19 cancer patient's characteristics. We determine whether differences exist in cumulative incidence and mortality of Covid-19 infection between cancer patients and general population in Madrid.. We reviewed 1069 medical records of all cancer patients admitted at Oncology department between Feb 1 and April 7, 2020. We described Covid-19 cumulative incidence, treatment outcome, mortality, and associated risk factors.. We detected 45/1069 Covid-19 diagnoses in cancer patients vs 42,450/6,662,000 in total population (p < 0.00001). Mortality rate: 19/45 cancer patients vs 5586/42,450 (p = 0.0001). Mortality was associated with older median age, adjusted by staging and histology (74 vs 63.5 years old, OR 1.06, p = 0.03). Patients who combined hydroxychloroquine and azithromycin presented 3/18 deaths, regardless of age, staging, histology, cancer treatment and comorbidities (OR 0.02, p = 0.03).. Cancer patients are vulnerable to Covid-19 with an increase in complications. Combined hydroxychloroquine and azithromycin is presented as a good treatment option.

Topics: Aged; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; Drug Combinations; Female; Humans; Hydroxychloroquine; Incidence; Male; Middle Aged; Neoplasms; Pandemics; Pneumonia, Viral; Risk Factors; SARS-CoV-2; Spain; Treatment Outcome

Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.. In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.. Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.. Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.. American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Topics: Aged; Antiviral Agents; Azithromycin; Betacoronavirus; Cause of Death; Comorbidity; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Databases, Factual; Female; Humans; Hydroxychloroquine; Male; Middle Aged; Neoplasms; Pandemics; Pneumonia, Viral; Prognosis; Risk Factors; SARS-CoV-2

Disease progression and treatment with hydroxychloroquine and azithromycin ere associated with increased all-cause 30-day mortality in patients with cancer compared with patients either in remission or with no evidence of disease, according to data presented during a 2020 American Society of Clinical Oncology Virtual Scientific Program press briefing.

Topics: Anti-Infective Agents; Azithromycin; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Disease Progression; Humans; Hydroxychloroquine; Mortality; Neoplasms; Pandemics; Pneumonia, Viral; Risk Assessment; SARS-CoV-2

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azithromycin; Cell Line, Tumor; Cisplatin; Clinical Trials, Phase II as Topic; COVID-19; COVID-19 Drug Treatment; Crizotinib; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Female; France; Humans; Hydroxychloroquine; Mice; Neoplasms; Oxaliplatin; Programmed Cell Death 1 Receptor; SARS-CoV-2

The proton pump inhibitor lansoprazole (LPZ) inhibits the growth of several cancer cell lines, including A549 and CAL 27. We previously reported that macrolide antibiotics such as azithromycin (AZM) and clarithromycin (CAM) potently inhibit autophagic flux and that combining AZM or CAM with the epidermal growth factor receptor inhibitors enhanced their antitumor effect against various cancer cells. In the present study, we conducted the combination treatment with LPZ and macrolide antibiotics against A549 and CAL 27 cells and evaluated cytotoxicity and morphological changes using cell proliferation and viability assays, flow cytometric analysis, immunoblotting, and morphological assessment. Combination therapy with LPZ and AZM greatly enhanced LPZ‑induced cell death, whereas treatment with AZM alone exhibited negligible cytotoxicity. The observed cytotoxic effect was not mediated through apoptosis or necroptosis. Transmission electron microscopy of A549 cells treated with the LPZ + AZM combination revealed morphological changes associated with necrosis and accumulated autolysosomes with undigested contents. Furthermore, the A549 cell line with ATG5 knockout exhibited complete inhibition of autophagosome formation, which did not affect LPZ + AZM treatment‑induced cytotoxicity, thus excluding the involvement of autophagy‑dependent cell death in LPZ + AZM treatment‑induced cell death. A549 cells treated with LPZ + AZM combination therapy retained the endosomal Alexa‑dextran for extended duration as compared to untreated control cells, thus indicating impairment of lysosomal digestion. Notably, lysosomal galectin‑3 puncta expression induced due to lysosomal membrane permeabilization was increased in cells treated with LPZ + AZM combination as compared to the treatment by either agent alone. Collectively, the present results revealed AZM‑induced autolysosome accumulation, potentiated LPZ‑mediated necrosis, and lysosomal membrane permeabilization, thus suggesting the potential clinical application of LPZ + AZM combination therapy for cancer treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy-Related Protein 5; Azithromycin; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Gene Knockout Techniques; Humans; Intracellular Membranes; Lansoprazole; Lysosomes; Microscopy, Electron, Transmission; Neoplasms; Permeability

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.

Topics: Aminoglycosides; Anti-Bacterial Agents; Base Sequence; DEAD-box RNA Helicases; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Models, Molecular; Molecular Sequence Data; Neoplasms; Ribonuclease III; Ribosomes; Tetracyclines

Papulopustular eruption (PPE) is the most common cutaneous side effect of epidermal growth factor receptor inhibitors (EGFRIs).. To document the efficacy and safety of pulsed azithromycin doses in the treatment of EGFRI-related PPE.. A retrospective analysis of patients under EGFRIs who exhibited at least grade 2 PPE and were intolerant or resistant to tetracyclines was performed. Treatment consisted of pulsed azithromycin doses of 500 mg daily for 3 consecutive days per week for at least 2 weeks.. Treatment with azithromycin showed a significant reduction in the number of lesions in 18/20 patients, with 11 showing complete resolution of the rash. No significant side effects were recorded. We did not observe any interactions with the targeted biological agents or any obvious compromise of the anticancer treatment.. Weekly pulses of azithromycin are effective and promote increased patient adhesion to the treatment. A prospective study is needed to confirm efficacy and safety of this convenient treatment.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azithromycin; Cetuximab; Drug Eruptions; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Female; Humans; Male; Middle Aged; Neoplasms; Panitumumab; Pulse Therapy, Drug; Quinazolines; Retrospective Studies; Time Factors

In order to evaluate the incidence rate and possible risk factors associated with AIDS-related malignancies and infections (ARMI) we performed data analysis of clinical charts of HIV patients in two hospital cohorts, that started high activity antiretroviral therapy (HAART) between July 2003 and October 2007. Trimethoprim-sulfamethoxazole and Azithromycin prophylaxis was provided according to current guidelines. We evaluated development of ARMI six months after-starting HAART and its association with clinical and epidemiological variables. Of 235 patients analyzed -118 women (50.2%) and 117 men (49.8%)- 11 presented ARMI: 3 pulmonary TB and 3 lymph nodes TB cases, 3 cases with meningeal Cryptococcus, one Chagas's disease presenting brain mass and one with non-Hodgkin lymphoma. ARMI incidence: 4.7%. A CD4 cell count < 100/150 was associated with risk of developing ARMI. The mean CD4 cell count was 73 in patients who developed ARMI and 143 in those who did not. No association was found with the other analyzed variables. In the CD4 cell count < 150 group one out of 4 patients with reactive serology presented Chagas's disease causing brain mass; none of the 46 patients with reactive serology presented toxoplasmosis encephalitis. The incidence rate of ARMI was 4.7%. TB in first place and cryptococcosis in second were the AIDS events more frequently observed. A low CD4 cell count was the only observed risk factor statistically associated with development of ARMI. The role of prophylaxis in this population should be re-evaluated.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Antiretroviral Therapy, Highly Active; Argentina; Azithromycin; CD4 Lymphocyte Count; Female; Humans; Male; Neoplasms; Odds Ratio; Retrospective Studies; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load

Topics: Anti-Bacterial Agents; Azithromycin; Cell Cycle; Clarithromycin; Depression, Chemical; Dose-Response Relationship, Drug; Humans; Neoplasms; Tumor Cells, Cultured

Topics: Anti-Bacterial Agents; Azithromycin; Biocompatible Materials; Cell Adhesion; Clarithromycin; Collagen; Drug Combinations; Flow Cytometry; Humans; Laminin; Neoplasms; Proteoglycans; Tumor Cells, Cultured