tetracycline and Carcinoma--Non-Small-Cell-Lung

Afatinib has shown long progression free survival and improvement in quality of life in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Although afatinib causes acneiform rash, it can be manageable. Tetracyclines are usually used to treat it; nonetheless, there is no trial that evaluates their prophylactic efficacy on afatinib induced-skin toxicities (AIST).. This open-label, randomized, controlled trial assessed the preventive effect of tetracycline for reducing afatinib-skin toxicities in NSCLC patients receiving afatinib 40 mg/day. Patients were randomly assigned to receive pre-emptive treatment with tetracycline 250 mg every 12h for 4 weeks or not. Reactive treatment in both groups included general dermatological recommendations such as use of skin moisturizers, sunscreen and topical steroids, according to toxicity severity. All patients were blindly monitored for skin toxicities by an expert dermatologist at the start of treatment with afatinib (day 0), weeks 2 and 4 of treatment. The protocol is registered on clinicaltrials.gov (NCT01880515).. We included 90 patients, no differences were found in clinical and dermatological baseline characteristics. Rash incidence of any grade, and grade ≥2 was less frequent in the pre-emptive arm vs. the control arm (44.5 vs. 75.6%, RR 0.4 [95% CI 0.17-0.99], p=0.046 and 15.6 vs. 35.6%, RR 0.35 [95% CI, 0.12-0.91], p=0.030, respectively). No difference was found in paronychia, xerosis, mucositis, folliculitis, and skin fissure. No adverse event was associated with tetracycline. Neither rash nor pre-emptive tetracycline impacted on response rate, progression-free or overall survivals.. Pre-emptive tetracycline was well tolerated and reduced the rash incidence and severity associated with afatinib in more than 60%.

Topics: Adult; Afatinib; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pre-Exposure Prophylaxis; Quinazolines; Risk Factors; Skin Diseases; Tetracycline

In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53([gln22ser23]), is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53([gln22ser23]). Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60-90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.

Topics: Antineoplastic Agents; Apoptosis; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Clone Cells; Colchicine; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Daunorubicin; DNA Damage; DNA, Neoplasm; Etoposide; Fluorouracil; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Lung Neoplasms; Models, Biological; Proline; Promoter Regions, Genetic; Protein Structure, Tertiary; Recombinant Fusion Proteins; Structure-Activity Relationship; Tetracycline; Transcription, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Topics: Adult; Carcinoma, Non-Small-Cell Lung; Drainage; Electrocardiography; Humans; Lung Neoplasms; Male; Middle Aged; Pericardial Effusion; Pericardium; Tetracycline