minocycline and Lung-Neoplasms

In patients with non-small cell lung cancer (NSCLC), concurrent chemoradiation therapy (CRT) exacerbates a cluster of difficult-to-manage symptoms, especially cancer-related fatigue. Minocycline is a readily available, low-cost antibiotic with antiinflammatory properties. We conducted a phase 2 randomized, double-blinded, placebo-controlled trial to investigate the effect of minocycline in reducing CRT-symptom burden in NSCLC.. Patients with NSCLC scheduled to receive CRT provided consent and were randomized to receive either minocycline (100 mg twice daily) or a matching placebo during 6 to 7 weeks of CRT. Patient-reported fatigue and other symptoms were assessed on MD Anderson Symptom Inventory weekly from the start of CRT for 12 weeks. The primary outcome was 12-week (±2 days) area under the curve for symptom burden, which was compared between treatment groups.. Forty of 49 enrolled patients (80%) were evaluable (19 on minocycline and 21 on placebo). There were no grade 3 + adverse events related to the study medication. Fatigue was significantly reduced in the minocycline group compared with placebo group during the 12-week trial period (area under the curve = 31.2 ± 14.2 vs 45.0 ± 20.9, P = .011), with a large effect size (Cohen's d = 0.77). Pain (Cohen's d = 0.54) and shortness of breath (Cohen's d = 0.55) were also significantly reduced in the minocycline group (all P < .05).. Minocycline during CRT for NSCLC was feasible, had a low toxicity profile, and yielded a clinically and statistically significant positive signal in reducing symptom burden related to NSCLC and CRT. This study is a proof of concept so a larger trial in CRT patients is warranted.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Double-Blind Method; Dyspnea; Fatigue; Female; Humans; Lung Neoplasms; Male; Middle Aged; Minocycline; Proof of Concept Study; Prospective Studies; Quality of Life

Erlotinib is an epidermal growth factor receptor inhibitor approved for patients with advanced non-small-cell lung cancer (NSCLC) whose epidermal growth factor receptor expression status is positive or unknown. Although it is efficacious, erlotinib can cause skin toxicity. This prospective, randomized phase III trial examined the effect of prophylactic treatment of erlotinib-induced skin rash.. Patients receiving erlotinib in the second- or third-line setting for advanced NSCLC were randomly assigned to prophylactic minocycline (100 mg twice per day for 4 weeks), reactive treatment (after rash developed, per grade of rash), or no treatment unless severe (grade 3). Rash incidence and severity, time to maximal rash, time to resolution, and overall survival (OS) were compared among treatment groups.. In all, 150 patients were randomly assigned, 50 to each of three treatment arms. The incidence of skin toxicity was 84% regardless of treatment arm. Prophylactic treatment with minocycline significantly lengthened the time to the most severe grade of rash. Grade 3 rash was significantly higher in the no-treatment arm. OS was not significantly different among treatment arms, but patients receiving prophylactic or reactive treatments had a longer OS (7.6 and 8 months, respectively) than those who received no rash treatment (6 months). Rash was not self-limiting.. The incidence of all grades of rash did not differ statistically among the three arms, so the trial was negative. The incidence of grade 3 skin toxicities was reduced in patients who were treated with prophylactic minocycline or reactive treatment. Efficacy was not compromised. Prophylactic minocycline and reactive treatment are both acceptable options for the necessary treatment of erlotinib-induced rash in the second- or third-line setting of metastatic NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Exanthema; Female; Humans; Lung Neoplasms; Male; Middle Aged; Minocycline; Prospective Studies; Protein Kinase Inhibitors

The aim of this report was to evaluate perioperative antibiotherapy and antiseptic irrigation of the operative site in the prevention of post-pneumonectomy empyema. From 1984 to 1986, 171 patients undergoing pneumonectomy at our institution for bronchogenic carcinoma were randomly selected in 2 groups: group I (85 patients) received a "classical" prophylaxis: irrigation of the operative site with saline, plus a 7-day antibiotherapy (minocycline 200 mg/24 h) started the evening following surgery; group II (86 patients): irrigation of the operative site was performed with Povidone iodine (dilution 5%); antibiotherapy (cefotiam was given for a short period (2 g intraoperatively, 2 g 12 hours and 24 hours following surgery). We used a "pragmatic" approach in order to choose, whatever the results would be, a type of perioperative antibiotherapy. We thus accepted the choice, without the help of statistical tests, of the therapy that would best prevent infection, and, if both regimens would demonstrate the same efficacy, to leave the choice at random. The only statistical test was to calculate the "gamma-risk" that we choose the worst among the 2 regimens. Although no significant difference in the overall infection rate was observed between the 2 groups, there were 9 empyemas (5 of those with bronchial fistula) in group I and 3 empyemas (2 of those with bronchial fistula) in group II. The cefotiam-povidone iodine regimen is thus better than the minocycline-saline regimen in the prevention of post-pneumonectomy empyema (3.5% v.s. 10.5%). The "gamma-risk", ie the probability that the minocycline-saline regimen is the best, calculated from these percentages, is 0.03.

Topics: Aged; Cefotiam; Drug Therapy, Combination; Humans; Lung Neoplasms; Middle Aged; Minocycline; Pneumonectomy; Postoperative Care; Povidone; Povidone-Iodine; Premedication

Cancer immunotherapies are powerful therapeutic options for cancer patients. To enhance the therapeutic effects of cancer immunotherapies, we plan to develop novel immunostimulatory drugs for use in combination with cancer immunotherapy. In the present study, we focused on tetracyclines, the effects of which are controversial for immunotherapy. We examined the effects of tetracyclines on human T cells in the peripheral blood of healthy donors and the tumor tissues of non-small cell lung cancer (NSCLC) patients. By using bispecific T-cell engager technology to assess the cytotoxicity of peripheral T cells against tumor cells, we showed that tetracyclines (minocycline, tetracycline, doxycycline, meclocycline, chlortetracycline, and demeclocycline) enhanced T-cell cytotoxicity through granzyme B expression and CD4+ and CD8+ T-cell proliferation. In analyses of the peripheral blood mononuclear cells (PBMCs) and lung tumor-infiltrated cells of NSCLC patients, we found that demeclocycline enhanced T-cell cytotoxicity not only in PBMCs, but also in lung tumor tissues. These results support the further application of tetracyclines to combination cancer immunotherapy.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Leukocytes, Mononuclear; Lung Neoplasms; Minocycline; T-Lymphocytes

While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline.. First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder.. Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically.. These results suggest that minocycline petrolatum applied locally prevents and repairs afatinib-induced skin disorders of non-small cell lung cancer patients. Histological examination of skin has provided insights into the mechanism of the occurrence of afatinib-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

Topics: Afatinib; Animals; Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; ErbB Receptors; Humans; Lung Neoplasms; Male; Mice; Minocycline; Protein Kinase Inhibitors; Quality of Life; Skin Diseases

Brain metastases are prevalent in various types of cancer and are often terminal, given the low efficacy of available therapies. Therefore, preventing them is of utmost clinical relevance, and prophylactic treatments are perhaps the most efficient strategy. Here, we show that systemic prophylactic administration of a toll-like receptor (TLR) 9 agonist, CpG-C, is effective against brain metastases. Acute and chronic systemic administration of CpG-C reduced tumor cell seeding and growth in the brain in three tumor models in mice, including metastasis of human and mouse lung cancer, and spontaneous melanoma-derived brain metastasis. Studying mechanisms underlying the therapeutic effects of CpG-C, we found that in the brain, unlike in the periphery, natural killer (NK) cells and monocytes are not involved in controlling metastasis. Next, we demonstrated that the systemically administered CpG-C is taken up by endothelial cells, astrocytes, and microglia, without affecting blood-brain barrier (BBB) integrity and tumor brain extravasation. In vitro assays pointed to microglia, but not astrocytes, as mediators of CpG- C effects through increased tumor killing and phagocytosis, mediated by direct microglia-tumor contact. In vivo, CpG-C-activated microglia displayed elevated mRNA expression levels of apoptosis-inducing and phagocytosis-related genes. Intravital imaging showed that CpG-C-activated microglia cells contact, kill, and phagocytize tumor cells in the early stages of tumor brain invasion more than nonactivated microglia. Blocking in vivo activation of microglia with minocycline, and depletion of microglia with a colony-stimulating factor 1 inhibitor, indicated that microglia mediate the antitumor effects of CpG-C. Overall, the results suggest prophylactic CpG-C treatment as a new intervention against brain metastasis, through an essential activation of microglia.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Colony-Stimulating Factors; Female; Humans; Lung Neoplasms; Male; Melanoma; Mice; Microglia; Minocycline; Oligodeoxyribonucleotides; Phagocytosis; Signal Transduction; Toll-Like Receptor 9

The management of skin toxicity is crucial for efficient afatinib treatment, but the role of tetracycline class antibiotics (TCs) in managing these rashes is relatively unknown.. We reviewed the clinical records of patients who were administered afatinib for the treatment of non-small cell lung cancer harboring epidermal growth factor receptor mutations between October 2014 and November 2016. Twenty-five patients, who received TCs for the management of afatinib-related skin disorders, were enrolled.. Minocycline was administered orally to participants. Afatinib-related toxic effects, such as rash, diarrhea, and paronychia, were observed in 92%, 92%, and 40% of cases, respectively. Although 24% of diarrhea and 4% of paronychia cases were rated grade 3 or higher, no severe cases of rash were observed during afatinib treatment. Of the 18 afatinib dose reductions, 14 (78%), three (17%), and one (6%) resulted from diarrhea, paronychia, and stomatitis, respectively; no patients required a dose reduction because of rash. When minocycline treatment started, 21 patients (84%) had a rash of grade 1 or less, and three patients had a grade 2 rash. A response to afatinib was observed in 18 patients (72%) and the median duration of afatinib administration was 501 days. An adverse event related to minocycline (grade 1 nausea) was observed in one patient.. A large proportion of the study patients started minocycline before grade 2 rash development and the severity of afatinib-related rash was lower than that previously reported. Oral TCs may be beneficial, especially if started early.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Diarrhea; Epidermal Growth Factor; Exanthema; Female; Humans; Lung Neoplasms; Male; Middle Aged; Minocycline; Mutation; Paronychia; Pyridines; Severity of Illness Index; Thiazoles

Lung adenocarcinoma is the most common pathologic pattern of lung cancer. During the past decades, a number of targeted agents have been explored to treat advanced lung adenocarcinoma. Recently, Crizotinib, the antagonist of anaplastic lymphoma kinase (ALK), has been widely used in ALK-rearranged lung cancer treatment. Crizotinib is generally well tolerated while its most frequent adverse events include visual disorders, gastrointestinal disturbances, cardiac and endocrine abnormalities. Rash caused by crizotinib is rarely seen, and there are few case reports of severe rash caused by crizotinib.. Here we report cases of an 81-year-old man and a 66-year-old woman with ALK-rearranged advanced lung adenocarcinoma. When patients came to our department, they both had crizotinib-induced severe rash.. Crizotinib was initiated as the 1st-line treatment without other therapies. We treated severe rash with traditional Chinese medicine (TCM) therapy called Zhiyang Pingfu liquid along with Western medicine. Zhiyang Pingfu liquid consists of Scutellaria baicalensis 20 g, Portulaca oleracea 30 g, Cortex Dictamni 30 g, Sophora flavescens 30 g, and other substances. Western medicine includes Minocycline hydrochloride tablets and Aprepitant capsules.. Both patients achieved a partial response when treated with crizotinib, and suffered from severe rash. With Zhiyang Pingfu liquid and Western medicine, their rash gradually disappeared with no sign of cancer progression. Also the male patient did not relieve after taking only antibiotics (standard therapy) and anti-allergic medicine.. Despite the dramatic benefit of crizotinib for patients with ALK rearrangement, crizotinib-induced severe rash needs to be dealt with caution. This is the 1st case in which TCM and Western medicine are used to successfully treat crizotinib-induced severe rash. The mechanism of crizotinib-induced rash deserves further attention in future research.

Topics: Adenocarcinoma of Lung; Aged; Aged, 80 and over; Anti-Bacterial Agents; Aprepitant; Crizotinib; Drug Therapy, Combination; Exanthema; Female; Humans; Lung Neoplasms; Male; Medicine, Chinese Traditional; Minocycline

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Dermatomyositis; Humans; Lung Neoplasms; Male; Methylprednisolone; Middle Aged; Minocycline; Pyoderma Gangrenosum; Small Cell Lung Carcinoma

Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer with a high mortality rate and still remains therapeutically a challenge. A strategy to target NSCLC is to identify agents that are effective against NSCLC cells while sparing normal cells. We show that tigecycline, an FDA-approved antibiotic drug, preferentially targets NSCLC cells. Tigecycline is effective in inhibiting proliferation and inducing apoptosis of multiple cell lines derived from two common NSCLC subtypes: adenocarcinoma and squamous cell carcinoma. Tigecycline also dose-dependently inhibits colony formation of NSCLC subpopulation of cells with highly proliferative and invasive properties. Compared to NSCLC cells, tigecycline affects proliferation and survival of normal fibroblast cells significantly to a less extent. More importantly, tigecycline significantly inhibits NSCLC tumor growth through decreasing proliferation and increasing apoptosis of tumor cells in vivo. Tigecycline significantly inhibits mitochondrial respiration, mitochondrial membrane potential, and ATP levels and increases reactive oxygen species (ROS), suggesting that tigecycline impairs mitochondrial functions. Our study suggests that tigecycline may be a useful therapeutic agent, and inhibiting mitochondrial functions may represent a new targeted therapy for NSCLC.

Topics: A549 Cells; Animals; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Dose-Response Relationship, Drug; Drug Delivery Systems; Humans; Lung Neoplasms; Mice; Mice, SCID; Minocycline; Mitochondria; Tigecycline; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Aged; Anti-Bacterial Agents; Carcinoma; Colonic Neoplasms; Drug Therapy, Combination; Female; Humans; Lung Neoplasms; Minocycline; Paraneoplastic Syndromes; Pyoderma Gangrenosum; Steroids

Minocycline is a semisynthetic tetracycline derivative; it has anti-inflammatory and anti-cancer effects distinct from its antimicrobial function. However, the molecular mechanism of minocycline-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Rad51 plays a central role in homologous recombination and high levels of Rad51 expression are observed in chemo- or radioresistant carcinomas. Our previous studies have shown that the MKK1/2-ERK1/2 signal pathway maintains the expression of Rad51 in NSCLC cells. In this study, minocycline treatment inhibited cell viability and proliferation of two NSCLC cells, A549 and H1975. Treatment with minocycline decreased Rad51 mRNA and protein levels through MKK1/2-ERK1/2 inactivation. Furthermore, expression of constitutively active MKK1 (MKK1-CA) vectors significantly rescued the decreased Rad51 protein and mRNA levels in minocycline-treated NSCLC cells. However, combined treatment with MKK1/2 inhibitor U0126 and minocycline further decreased the Rad51 expression and cell viability of NSCLC cells. Knocking down Rad51 expression by transfection with small interfering RNA of Rad51 enhanced the cytotoxicity and cell growth inhibition of minocycline. Mitomycin C (MMC) is typically used as a first or second line regimen to treat NSCLC. Compared to a single agent alone, MMC combined with minocycline resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-ERK1/2, and reduced Rad51 protein levels. Overexpression of MKK1-CA or Flag-tagged Rad51 could reverse the minocycline and MMC-induced synergistic cytotoxicity. These findings may have implications for the rational design of future drug regimens incorporating minocycline and MMC for the treatment of NSCLC.

Topics: Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Synergism; Humans; Lung Neoplasms; MAP Kinase Signaling System; Minocycline; Mitomycin; Rad51 Recombinase

A relatively newer class of chemotherapy agents, known as the epidermal growth factor receptor inhibitors (EGF-RIs), is being used to treat advanced stages of solid tumors. Acneiform eruptions are a frequent adverse effect and one which has been associated with increased survival in some studies. We describe 3 patients who presented shortly after initiation of EGF-RI therapy. Characteristics included an absence of comedones, facial and truncal involvement, and a perifollicular lymphoneutrophilic infiltrate detected on biopsy. Lesion counts were reduced with topical adapalene and oral tetracyclines in two patients. Patient 3 had dramatic clearance with low-dose isotretinoin (20 mg daily) until completion of EGF-RI therapy. Acneiform eruptions are a common adverse reaction to EGF-RI therapy and can be treated with traditional acne therapy. This should not be considered a drug hypersensitivity eruption or allergy, and patients should continue therapy. For patients with severe eruptions, oral isotretinoin is a consideration.

Topics: Acne Vulgaris; Adapalene; Administration, Oral; Administration, Topical; Adult; Anti-Bacterial Agents; Antineoplastic Agents; Colonic Neoplasms; Dermatologic Agents; Dose-Response Relationship, Drug; ErbB Receptors; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Minocycline; Naphthalenes

We investigated the effectiveness and complications of intrathoracic infusion with a combination of cisplatin, OK-432, and minocycline for malignant pleural effusion. All patients were hospitalized with chest tube drainage of pleural effusion until the daily drainage volume was less than 100 ml. Twenty-five mg of minocycline, 1 to 3 KE of OK-432, and 5 to 10 mg of cisplatin were instilled into the pleural space. The administration was repeated until drainage effusion disappeared. Therapeutic effect was evaluated according to the following criteria: (1) excellent, no fluid reaccumulation for at least 4 weeks as determined by chest radiogram and clinical evaluation; (2) effective, fluid reaccumulation less than 50% of original effusion with no need of thoracentesis for symptomatic relief within 4 weeks after treatment; and (3) failure, reaccumulation of more than 50% of the original effusion requiring thoracentesis to relieve symptoms within 4 weeks of treatment. Twelve patients with malignant effusion received the combination treatment; 11 patients had primary lung cancer and one had metastatic lung tumor from cancer of the rectum. In all cases, the histology or cytology revealed adenocarcinoma. Eleven of the 12 patients had an excellent response with relief of clinical symptoms. The remaining case failed to show any improvement. Complications such as local pain, fever, nausea, and vomiting were mild and transient. We conclude that combination administration of low-dose minocycline, OK-432, and cisplatin into the thoracic cavity for malignant effusion is an effective alternative treatment with the potential for improvement of the general condition and reduced morbidity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Drainage; Drug Administration Schedule; Female; Humans; Infusions, Intralesional; Lung Neoplasms; Male; Middle Aged; Minocycline; Picibanil; Pleural Effusion, Malignant; Thoracic Cavity

A 58-year-old man was admitted to our hospital because of an abnormal shadow found on chest radiography. Chest radiographs and chest CT on admission showed a bulla with a niveau and infiltration in the right upper lobe. Smear of sputum and bronchial lavage were negative for acid-fast bacilli. Despite treatment with meropenem and clindamycin, the infiltrating shadow worsened. Since bronchial lavage and sputum culture were positive for M. fortuitum, these drugs were replaced with minocycline and imipenem. Thereafter, the shadow on the chest radiograph improved. After discharge, outpatient treatment with clarithromycin and levofloxacin was continued. After 4 months, the residual tumor shadow in the right upper lobe gradually grew. When a CT-guided transcutaneous needle lung biopsy was undertaken, malignant cells were found. Right upper lobectomy was performed. Pathological examination of the lesion demonstrated small-cell lung cancer. If a lesion does not change after nontuberculous mycobacteria treatment, the physician should consider other lesions such as lung cancer.

Topics: Anti-Bacterial Agents; Carcinoma, Small Cell; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Humans; Imipenem; Lung Neoplasms; Male; Middle Aged; Minocycline; Mycobacterium fortuitum; Mycobacterium Infections, Nontuberculous; Radiography, Thoracic; Tomography, X-Ray Computed; Tuberculosis, Pulmonary

It has been known that treatments of post-pneumonectomy empyema are difficult. We report a successful case of irrigation for the post-pneumonectomy. The patient was 68-year-old man with advanced lung cancer. He underwent induction chemoradiotherapy following by pneumonectomy of the right side. A few days later after the chest drain was withdrawn, spike fever appeared. Empyema was suspected, so a 28 Fr diameter double lumen chest drain was intubated again. Turbid effusion was discharged through the drain, in which methicillin-resistant staphylococcus aureus (MRSA) was cultured. Irrigation using a lot of saline and acid electrolyzed water started. A month later, irrigator through the drain was looking clear, however, MRSA was cultured so far. After putting minomycine into the irrigator, MRSA died away. This physical and chemical irrigations were effective.

Topics: Adenocarcinoma; Aged; Empyema, Pleural; Humans; Lung Neoplasms; Male; Methicillin Resistance; Minocycline; Pneumonectomy; Postoperative Complications; Staphylococcal Infections; Therapeutic Irrigation

Eleven patients with massive effusion due to pleuritis carcinomatosa were treated by tube drainage, followed by instillation of OK-432 and minocycline for pleurodesis. Pleural immunological and chemical reactions of adhesion were strongly induced by the use of these adhesive agents. As a result, pleural effusion was diminished in all patients without recurrence, allowing the drainage tubes to be successfully removed. As severe adverse effects following this course of therapy, high fever was observed in all patients, and acute renal failure in one. Blood chemical data from the patients revealed an increase in the number of granulocytes with a high level of interleukin-6 one day after instillation. These findings suggested that the symptoms of general inflammation were induced by local pleural inflammation. The median survival period was 253.7 days for 5 patients who were sufficiently fit to be discharged from our hospital. This was better than the historical average for the patients with uncontrolled pleural effusion. In conclusion, it was possible to control malignant pleural effusion and achieve longer survival periods through the optimal management of tube drainage and instillation of adhesion-inducing agents.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antineoplastic Agents; Drug Therapy, Combination; Female; Humans; Lung Neoplasms; Male; Middle Aged; Minocycline; Picibanil; Pleura; Pleural Effusion, Malignant

Topics: Animals; Anti-Bacterial Agents; Carcinoma, Renal Cell; Endothelial Growth Factors; Fibroblast Growth Factor 2; Kidney Neoplasms; Lung Neoplasms; Lymphokines; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Minocycline; Neoplasm Invasiveness; Neoplasm Metastasis; Protease Inhibitors; Statistics, Nonparametric; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

TNP-740, minocycline, suramin and genistein have demonstrated antiangiogenic activity in various experimental systems. The effect of these agents alone and in two agent combinations on the number of intratumoral vessels and response to cytotoxic anticancer therapies was assessed in animals bearing the Lewis lung carcinoma. Treatment with each of the antiangiogenic agents alone and in two agent combinations decreased the number of intratumoral vessels visualized by CD31 or Factor VIII staining to 30% to 50% of the number in the untreated control tumors. In general, the antiangiogenic agents are more effective adjuvants to cytotoxic therapies when used as two agent combinations than as single agents. The most effective antiangiogenic combinations were: TNP-470/minocycline > TNP-470/genistein > TNP-470/suramin. The increases in the response of the primary tumor to cyclophosphamide, adriamycin, CDDP, BCNU, x-rays or 5-fluorouracil and the lung metastases occur to about the same level with the addition of antiangiogenic agents to the therapies. With the treatment combination TNP-470/minocycline/cyclophosphamide 40% of the animals were cured. The results of these studies indicate that antiangiogenic agents can be very useful additions to treatment regimens for solid tumors.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Lewis Lung; Carmustine; Cell Division; Cisplatin; Cyclohexanes; Cyclophosphamide; Doxorubicin; Drug Synergism; Genistein; Isoflavones; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Minocycline; Neoplasm Invasiveness; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Random Allocation; Sesquiterpenes; Suramin

Boanmycin (bleomycin A6, BAM) was found to markedly inhibit the spontaneous pulmonary metastasis of Lewis carcinoma in mice. Compared at equitoxic doses (1/9 LD50), BAM was more effective than mitomycin. Minocycline (MNO) at 5 mg.kg-1 showed no inhibition on the growth of sc transplanted Lewis primary tumor; however, it markedly potentiated the antimetastatic effect of BAM. Treated with BAM (5 mg.kg-1) alone, the number of total metastatic foci and that of large foci (> 2 mm in diameter) in the lung were suppressed by 67% and 85%, respectively. When BAM was used in combination with MNO, the number of those foci was further reduced by 88% and 100%, respectively. By NAG enzyme assay, MNO was not cytotoxic and showed no synergism with BAM against PG cells, a cell line derived from a highly metastatic human giant cell carcinoma of the lung. Determined by ELISA with a monoclonal antibody, the expression of type IV collagenase in PG cells was remarkably inhibited by MNO. The intracellular free Ca2+ level in PG cells was reduced from 76.7 nmol.L-1 to 42.2 nmol.L-1 by MNO treatment. The study suggests that the combination of boanmycin and minocycline may be useful for control of tumor metastasis and the inhibition of type IV collagenase expression may be involved in the mechanism of minocycline potentiation.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Carcinoma, Giant Cell; Carcinoma, Lewis Lung; Drug Synergism; Female; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Minocycline; Tumor Cells, Cultured

Like many clinical non-small-cell lung cancers, the Lewis lung carcinoma produces prostaglandins. The Lewis lung carcinoma was used as a model of both primary and metastatic disease to assess the ability of cyclooxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indomethacin), the collagenase inhibitor minocycline, and the lipoxygenase inhibitor phenidone to act as modulators of cytotoxic cancer therapies. Although none of the single modulators given i.p. daily on days 4-18 altered tumor growth or the number of metastases found on day 20, modulator combinations consisting of minocycline/a cyclooxygenase inhibitor and, especially, of phenidone/a cyclooxygenase inhibitor resulted in modest tumor growth delay and a decreased number of lung metastases on day 20. The most effective modulators of cisplatin (CDDP) were phenidone/sulindac and phenidone/indomethacin, which led to 2.4- to 2.5-fold increases in the tumor growth delay produced by CDDP. The most effective modulations of cyclophosphamide resulted from administration of minocycline, minocycline/sulindac, or phenidone/sulindac and led to 2.0- to 2.1-fold increases in tumor growth delay by cyclophosphamide. The most effective modulators of melphalan produced 4.5- to 4.7-fold increases in tumor growth delay by the drug and were minocycline/sulindac, minocycline/mefenamic acid, and phenidone/sulindac. The most effective modulation of carmustine (BCNU) was obtained with minocycline/sulindac and minocycline/diflunisal leading to 2.8- to 3.1-fold increases in tumor growth delay by BCNU. Finally, the most effective modulation of radiation was obtained with minocycline/sulindac and phenidone/sulindac and resulted in 2.8- to 3.3-fold increases in tumor growth delay by radiation. The modulator combination that along with the cytotoxic therapies was most effective against metastatic disease was phenidone/mefenamic acid. There was no clear relationship between effective modulation of the cancer therapies and the degree of reduction in serum levels of prostaglandin E2 and leukotriene B4 by the agents in Lewis lung tumor bearing mice.

Topics: Animals; Antineoplastic Agents; Cyclooxygenase Inhibitors; Dinoprostone; Drug Synergism; Leukotriene B4; Lipoxygenase Inhibitors; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Minocycline; Neoplasm Transplantation; Pyrazoles; Tumor Cells, Cultured

Degradation of the extracellular matrix by metalloproteinases is a critical phenomenon in cancer invasion and metastasis. Recent studies have revealed that minocycline (minocycline hydrochloride, a tetracycline) suppresses in vivo and in vitro mammalian collagenolytic activity. We investigated whether minocycline inhibited in vitro invasion and experimental pulmonary metastasis in subline-2 of streptozotocin-induced mouse renal adenocarcinoma (MRAC-PM2) cells. In vitro invasion assay demonstrated that treatment with 0.5 microgram/ml or 5.0 micrograms/ml minocycline significantly inhibited the invasion of MRAC-PM2 cells. In addition, intraperitoneal administration of 0.5 mg per mouse minocycline reduced the number of metastatic nodules in the lung when MRAC-PM2 cells were injected intravenously. Minocycline also suppressed type IV collagenolytic activity of the cells. However, the drug did not affect [3H]-thymidine uptake, growth of subcutaneously inoculated cells, attachment to the extracellular matrices, or haptotactic migration of the cells. These results indicated that the inhibitory action of type IV collagen degradation by minocycline can contribute, in part, to suppression of the in vitro invasion and metastatic potential of MRAC-PM2 cells.

Topics: Adenocarcinoma; Animals; Cell Adhesion; Collagen; DNA, Neoplasm; In Vitro Techniques; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred Strains; Minocycline; Neoplasm Invasiveness; Neoplasm Transplantation; Streptozocin; Tumor Cells, Cultured

Tetrahydrocortisol, beta-cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 microM, 24 h) and beta-cyclodextrin tetradecasulfate (100 microM, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 microM, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studied. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/beta-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14 x 5 mg/kg, days 4-18) and cyclophosphamide (3 x 150 mg/kg, days 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/beta-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Cell Division; Cell Hypoxia; Cyclodextrins; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C57BL; Minocycline; Tetrahydrocortisol; Tumor Cells, Cultured

The formation of a blood supply (angiogenesis) is critical to the growth of solid tumors. The naturally occurring steroid tetrahydrocortisol, the synthetic cyclodextrin derivative beta-cyclodextrin tetradecasulfate, and the tetracycline derivative minocycline have antiangiogenic activity. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate in a 1:1 molar ratio by continuous infusion over 14 days and minocycline administered i.p. over 14 days from day 4 to day 18 postimplantation of the Lewis lung carcinoma significantly increased the growth delay of the primary tumor after treatment with cis-diamminedichloroplatinum(II), melphalan, cyclophosphamide, Adriamycin, bleomycin, and radiation therapy administered in standard regimens. Addition of the antiangiogenic agents to treatment with the cytotoxic therapies not only reduced the number of lung metastases formed from the primary tumor but also reduced the number of large metastases. Five of 12 animals treated with the antiangiogenic modulators and cyclophosphamide were long-term survivors (> 120 days). Thus, antiangiogenic therapies can potentiate the efficacy of standard anticancer therapies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Bleomycin; Cisplatin; Cyclodextrins; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Lung Neoplasms; Mice; Mice, Inbred C57BL; Minocycline; Neoplasm Transplantation; Tetrahydrocortisol; Tumor Cells, Cultured

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Cells; Cell Survival; Combined Modality Therapy; Cyclophosphamide; Fibrosarcoma; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Minocycline; Tumor Cells, Cultured

The penetration of minocycline into different lung tissues and bronchial mucus was studied in 17 patients undergoing pulmonary surgery for cancer. The patients received oral minocycline 100 mg at night for 3 days preceding surgery. Minocycline concentrations were measured in plasma samples collected before the operation and in tissues and mucus taken from in and around the part of the lung that was surgically removed. Mean tissue or mucus concentration to plasma concentration ratios were 3.78 +/- 1.10 for lung parenchyma, 4.04 +/- 1.31 for bronchial walls, 3.37 +/- 1.00 for pulmonary arterial walls, 1.99 +/- 1.80 for intraluminal mucus collected from bronchi located in healthy tissue proximal to the tumour, 5.16 +/- 3.26 for intraluminal mucus collected in a bronchus distal to the tumour, and 3.06 +/- 1.99 for catheter-collected mucus from the trachea and principal bronchi. These results indicate that minocycline is found in high concentration in all types of lung tissue and mucus in man.

Topics: Adult; Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Minocycline; Tissue Distribution

Minocycline pleurodesis with intrapleural pretreatment of lidocaine (150 mg) was performed on 19 patients. Minocycline was instilled into the pleural space for postoperative air leakage in 12 patients and control of malignant pleural effusion in 7 patients. Postoperative air leakage persisted longer than seven days was indicated instillation of minocycline (300 mg) with thoracostomy drainage. Satisfactory results were obtained in 11 of the 12 patients (92%) treated with this method. In 7 patients to control malignant pleural effusion, only one of these patients had recurrence of pleural effusion. Seventeen patients of all 19 subjects were free of pain following pleurodesis. None of these patients had a side effect of lidocaine. In conclusion of instillation, minocycline with thoracostomy drainage is a safe and an effective technique.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Drug Evaluation; Female; Humans; Instillation, Drug; Lung Neoplasms; Male; Middle Aged; Minocycline; Pleural Effusion; Pneumonectomy; Pneumothorax; Postoperative Complications; Tetracyclines; Thorax

In order to investigate the possible mechanism for the therapeutic efficacy of tetracycline antibiotics against malignant pleural effusion, the effect of minocycline (MC), one of this type of antibiotic, on in vitro growth of tumor cells was examined. As a result, it was found that MC caused complete growth inhibition of various tumor cell lines at concentration of 10-20 micrograms/ml, but this action was reversible, suggesting that considerably long exposure time would be needed for these drugs to kill the tumor cells in vivo at a relatively low concentration. On the other hand, when a relatively high concentration of 100 micrograms/ml was applied, MC induced irreversible inhibition of cell growth even if the exposure time was comparatively short. Since 4 human lung tumor cell lines examined exhibited high sensitivity to these antibiotics, it seems possible that their direct administration in the form of a high-concentration solution into the pleural cavity would result in a direct cytostatic effect on tumor cells in clinical therapy.

Topics: Animals; Cell Division; Cell Line; Cell Survival; Cells, Cultured; Humans; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Lung Neoplasms; Mice; Minocycline; Pleural Effusion; Tetracyclines

Topics: Adult; Aged; Carcinoma; Female; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Lung Neoplasms; Lymph Node Excision; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Surgical Wound Infection; Tetracyclines