minocycline and Leukemia

To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Genes, Mitochondrial; Humans; Leukemia; Mice; Minocycline; Mitochondria; Mitochondrial Proteins; Neoplastic Stem Cells; Peptide Elongation Factor Tu; Protein Biosynthesis; RNA, Small Interfering; Saccharomyces cerevisiae; Tigecycline

Tigecycline, the first in a new class of glycylcyclines, has been approved for the treatment of complicated skin and skin structure and intraabdominal infections in adults. However, clinical data on its safety and effectiveness in cancer patients are lacking. We reviewed the records of all cancer patients treated with tigecycline for more than 48 hours between June 2005 and September 2006 at our institution and identified 110 consecutive cases (median age, 58 yr; range, 18-81 yr). We collected data on demographics, cancer type, tigecycline indication, microbiologic characteristics, side effects, and outcome. Sixty-four (58%) patients had hematologic malignancies; 27 patients had undergone hematopoietic stem cell transplantation. Thirty-one (28%) patients had neutropenia, and 62 (56%) were in the intensive care unit at the start of therapy. Most patients (106 [96%]) received tigecycline as a second-line agent (after not responding to other broad-spectrum antibiotics), and 101 (92%) received it in combination with an antipseudomonal drug. The mean duration of therapy was 11 days (range, 3-35 d). Sixty-six (60%) patients received tigecycline for refractory pneumonia, 19 (17%) had bacteremia, 9 (8%) had intraabdominal infections, and 7 (6%) had complicated skin and soft tissue infections. Fifty (45%) patients had microbiologically documented infections, and the remaining patients had negative cultures at the start of therapy.An overall clinical response was noted in 70 (64%) patients. More clinical responses were seen in patients with bacteremia than in those with pneumonia (79% vs. 51%; p = 0.029). Patients with microbiologically documented infections had significantly higher clinical response rates than patients with non-microbiologically documented infections (73% vs. 55%; p = 0.047). Forty (36%) patients did not respond to treatment; 36 of these patients died of active infection during tigecycline therapy. Patients with pneumonia had a significantly higher mortality rate than patients with bacteremia (44% vs. 16%; p = 0.026). During the 60 days of follow-up from the date of clinical response, patients with pneumonia had significantly shorter survival durations than patients with other infections. Of the 42 patients who were not on antiemetics or ventilator support at the start of tigecycline therapy, 2 (5%) experienced mild nausea, and 1 (2%) experienced nausea and vomiting. Only 4 (4%) patients overall experienced diarrhea during tigecycline therapy, all

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Bacterial Infections; Female; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Leukemia; Lymphoma; Male; Middle Aged; Minocycline; Nausea; Pneumonia, Bacterial; Retrospective Studies; Tigecycline; Treatment Outcome; Vomiting; Young Adult

In this retrospective evaluation of the 4-year clinical use of minocycline and rifampin-impregnated catheters in bone marrow transplantation (BMT) patients, we report low risk of development of staphylococcal resistance to the antibiotics coating the catheters and efficacy in preventing primary staphylococcal bloodstream infections.

Topics: Adult; Anti-Bacterial Agents; Antibiotics, Antitubercular; Bone Marrow Transplantation; Catheterization, Central Venous; Catheters, Indwelling; Cohort Studies; Cross Infection; Drug Delivery Systems; Drug Resistance; Female; Humans; Infection Control; Leukemia; Male; Middle Aged; Minocycline; Neutropenia; Rifampin; Staphylococcal Infections; Texas

Mycoplasmal contamination of cell culture systems continues to present major problems for basic research and for manufacturing of bioproducts. Previous work suggested that certain antibiotics have strong anti-mycoplasma properties and raised the prospect that the technically rather simple antibiotic treatment may be an appropriate means for mycoplasma eradication. We have developed and validated an effective strategy to eliminate mycoplasma from chronically infected cell cultures using antibiotics which have shown strong activity against these contaminants. Here, we describe our experience with the treatment of 123 consecutive mycoplasma-positive leukemia-lymphoma cell lines, comparing five different antibiotic regimens (in total 433 treatments). We optimized the antibiotic dose schedules and the duration of treatments. The various antibiotic treatments which were employed in parallel had a high efficacy, as 71% to 86% of the infected cultures were cleansed. Treatment failure may result from the resistance of the mycoplasmas to antibiotic therapy and the inability of the eukaryotic cells to survive the cytotoxic effects of the antibiotics. Resistance to mycoplasma eradication was observed in 3% to 20% of the cultures. Loss of the cell culture caused by cytotoxicity was seen in 3% to 11% of the treatments. With regard to the overall outcome, 96% of the cell lines were rendered mycoplasma-free with at least one of the antibiotic treatments and were permanently cured. In conclusion, antibiotic treatment represents the most practical and efficient option to cleanse mycoplasma-positive cell lines.

Topics: Algorithms; Anti-Bacterial Agents; Anti-Infective Agents; Cell Culture Techniques; Ciprofloxacin; Culture Media; Diterpenes; Drug Resistance; Drug Resistance, Multiple, Bacterial; Enrofloxacin; Fluoroquinolones; Humans; Leukemia; Lymphoma; Minocycline; Mycoplasma; Quinolones; Suspensions; Tumor Cells, Cultured

19 suspension cell lines were treated with antibiotics for elimination of chronic contamination with mycoplasma. We compared the efficiency, cytotoxicity and cross-resistance of the commercially available antibiotics MRA (Mycoplasma Removal Agent, a quinolone derivative and DNA gyrase inhibitor), Ciprobay (ciprofloxacin, also a quinolone derivative and DNA gyrase inhibitor), and BM-cyclin (a combination of tiamulin, a pleuromutilin derivative, and minocycline, a tetracycline derivative, both inhibitors of protein synthesis on ribosomes). Contaminants were eliminated in all 19 cell lines by BM-Cyclin. Only 74% of the cell lines were cleared of contamination by both MRA and Ciprobay. Successful treatment was monitored by three mycoplasma detection assays. Cross-resistance was noted between MRA and Ciprobay in four of the five cell lines not cleared by either reagent. This resistance could, however, be overcome by consecutive exposure to BM-cyclin. Employed at the recommended concentrations, the antibiotics did not cause marked cytotoxicity, but the growth of the cells was affected to various degrees by some antibiotics. The elimination of mycoplasma from chronically contaminated cell lines is an effective alternative to other treatment protocols, but is cost-intensive and time-consuming; lasting damaging effects of the treatments on the eukaryotic cells cannot be excluded. Long-term post-treatment monitoring is mandatory, since contaminants may only be suppressed and then recur.

Topics: Anti-Bacterial Agents; Cell Division; Cell Line; Ciprofloxacin; Diterpenes; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Leukemia; Minocycline; Mycoplasma Infections; Quinolones

From January 1978 to August 1990, Staphylococcus aureus bacteremia (SAB) were identified in 31 patients with hematological malignancies at Jichi Medical School hospital. Mortality due to SAB was 48.4% (15/31). Of the variables analyzed, four factors were significantly associated with a poor prognosis; elderly age (p = 0.015), high granulocyte count (more than 500/microliters) (p = 0.015), presence of DIC (p = 0.011) and presence of pneumonia (p = 0.023). The incidence of methicillin-resistant SAB was 32.3% (10/31) and the first patient developed in 1985. Although not statistically significant, there was a trend of higher mortality for methicillin-resistant SAB (70%) than for methicillin-sensitive SAB (38.1%). Most strains of methicillin-resistant Staphylococcus aureus were sensitive to minocycline, chloramphenicol and vancomycin.

Topics: Adult; Aged; Aged, 80 and over; Chloramphenicol; Female; Humans; Leukemia; Male; Methicillin Resistance; Middle Aged; Minocycline; Prognosis; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Topics: Acute Disease; Adult; Aged; Anemia, Aplastic; Bacterial Infections; Carbenicillin; Cefazolin; Female; Humans; Infusions, Parenteral; Leukemia; Male; Middle Aged; Minocycline; Multiple Myeloma; Penicillin Resistance; Sulbenicillin; Tetracyclines

Topics: Bacteria; Bacterial Infections; Doxycycline; Humans; Leukemia; Minocycline; Neoplasms; Tetracycline