ABSTRACT
BACKGROUND: Bexarotene was evaluated in treating advanced non small cell lung cancer (NSCLC) in two phase III trials. Although a significant survival benefit was not observed for the overall bexarotene-treated population (617 patients), a third of bexarotene-treated patients who developed high-grade hypertriglyceridemia exhibited significantly longer survival. PATIENTS AND METHODS: In order to identify genomic polymorphisms that could serve as potential predictive biomarkers for response and improved survival in NSCLC patients, DNA samples extracted from plasma archived from 403 patients were genotyped using Affymetrix 500K whole genome SNP arrays and/or Sequenom iPLEX™ assays. RESULTS: Fourteen SNPs were identified on nine loci that showed significant associations with high-grade hypertriglyceridemia induced by bexarotene. Four such single nucleotide polymorphisms (SNPs) reside on the region upstream of solute carrier family 10, member 2 (SLC10A2), and one SNP is located close to lymphocyte cytosolic protein 1 (LCP1), whose expression correlated with the activity of bexarotene in tumor cells. CONCLUSION: We identified novel polymorphisms exhibiting significant association with bexarotene induced hypertriglyceridemia, implicating their potential in predicting bexarotene-improved survival response.
Subject(s)
Carcinoma, Non-Small-Cell Lung/blood , Hypertriglyceridemia/chemically induced , Hypertriglyceridemia/genetics , Lung Neoplasms/blood , Tetrahydronaphthalenes/adverse effects , Bexarotene , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Case-Control Studies , Clinical Trials, Phase III as Topic , DNA/blood , DNA/genetics , Female , Genetic Predisposition to Disease , Humans , Hypertriglyceridemia/blood , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide , Tetrahydronaphthalenes/therapeutic useABSTRACT
PURPOSE This phase III, placebo-controlled, randomized trial was designed to investigate efficacy and safety of two doses of denileukin diftitox (DD; DAB(389)-interleukin-2 [IL-2]), a recombinant fusion protein targeting IL-2 receptor-expressing malignant T lymphocytes, in patients with stage IA to III, CD25 assay-positive cutaneous T-cell lymphoma (CTCL), including the mycosis fungoides and Sézary syndrome forms of the disease, who had received up to three prior therapies. The primary end point was overall response rate (ORR). PATIENTS AND METHODS Patients (N = 144) with biopsy-confirmed, CD25 assay-positive CTCL were randomly assigned to DD 9 microg/kg/d (n = 45), DD 18 microg/kg/d (n = 55), or placebo infusions (n = 44), administered for 5 consecutive days every 3 weeks for up to eight cycles. Patients were monitored for drug efficacy, clinical benefit, and safety of DD. RESULTS ORR was 44% for all participants treated with DD (n = 100; 10% complete response [CR] and 34% partial response [PR]) compared with 15.9% for placebo-treated patients (2% CR and 13.6% PR). ORR was higher in the 18 microg/kg/d group versus the 9 microg/kg/d group (49.1% v 37.8%, respectively), and both doses were significantly superior to placebo. Progression-free survival (PFS) was significantly longer (median, > 2 years) for both DD doses compared with placebo (median, 124 days; P < .001). Rates of moderately severe and severe adverse events (AEs) were slightly higher in the DD groups, whereas moderate and mild AEs were similar to placebo. No statistical differences were observed for drug-related serious AEs. CONCLUSION DD had a significant and durable effect on ORR and PFS with an acceptable safety profile in patients with early- and late-stage CTCL.
Subject(s)
Antineoplastic Agents/therapeutic use , Diphtheria Toxin/therapeutic use , Interleukin-2/therapeutic use , Lymphoma, T-Cell, Cutaneous/drug therapy , Recombinant Fusion Proteins/metabolism , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , International Agencies , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/pathology , Male , Middle Aged , Neoplasm Staging , Placebos , Recombinant Fusion Proteins/therapeutic use , Safety , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Survival Rate , Treatment Outcome , Young AdultABSTRACT
PURPOSE: The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m(2)/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted. RESULTS: A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss >or= 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm. CONCLUSION: Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/secondary , Lung Neoplasms/drug therapy , Bexarotene , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Drug Administration Schedule , Humans , Hypertriglyceridemia/chemically induced , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Transplantation , Paclitaxel/administration & dosage , Survival Analysis , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effectsABSTRACT
PURPOSE: This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted. RESULTS: A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm). CONCLUSION: The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Triglycerides/blood , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Bexarotene , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/secondary , Cisplatin/administration & dosage , Disease Progression , Female , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/chemically induced , Hypertriglyceridemia/mortality , Lung Neoplasms/blood , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Survival Rate , Tetrahydronaphthalenes/adverse effects , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , VinorelbineABSTRACT
Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.
Subject(s)
Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Benzopyrans/adverse effects , Benzopyrans/therapeutic use , Benzylidene Compounds/adverse effects , Benzylidene Compounds/therapeutic use , Receptors, Glucocorticoid/agonists , Animals , Arthritis, Rheumatoid/drug therapy , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Ligands , Male , Models, Biological , Prednisolone/adverse effects , Prednisolone/therapeutic use , Rats , Rats, Inbred Lew , Rats, Inbred WKY , Rats, Sprague-Dawley , Spodoptera , Substrate SpecificityABSTRACT
Although it is evident that androgens increase muscle mass and strength, little is known about the critical molecular targets of androgens in skeletal muscle. In rodents, the skeletal alpha-actin gene is a tissue-specific gene expressed only in the levator ani and other skeletal muscles but not in the prostate or preputial gland, the well-known androgen target tissue. We identified tissue-specific androgen-regulated genes in the skeletal muscle in rats after oral administration of androgens and focused on androgen-dependent up-regulation of the skeletal alpha-actin gene. To investigate the mechanism of action, an in vitro system with various cell lines and a series of deletion mutants of the alpha-actin promoter were used. The human skeletal alpha-actin promoter was activated by androgens in the muscle cell line C2C12 but not in the liver, prostate, or breast cancer cell lines in which exogenous human androgen receptor is expressed. The sequence of the promoter is sufficient for cell-specific androgen response, providing a model for the tissue specificity demonstrated in vivo. Using a series of deletion mutants, the androgen response can be maintained using just the proximal promoter region. The importance of androgen regulation of this small portion of the human skeletal alpha-actin promoter was demonstrated by the correlation between muscle and the alpha-actin promoter activity for an array of selective androgen receptor modulators (SARMs), including an orally active SARM LGD2226. Taken together, the results suggest that the regulation of skeletal alpha-actin by androgens/SARMs may represent an important model system for understanding androgen anabolic action in the muscle.
Subject(s)
Actins/metabolism , Androgens/physiology , Muscle, Skeletal/metabolism , Actins/genetics , Aminoquinolines/pharmacology , Animals , Base Sequence , Cell Line , Cell Line, Tumor , Dihydrotestosterone/pharmacology , Gene Expression Regulation , Humans , Male , Mice , Models, Animal , Molecular Sequence Data , Promoter Regions, Genetic , Quinolones/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Androgen/metabolism , TransfectionABSTRACT
STUDY OBJECTIVE: To investigate the effect of once-a-day extended release of morphine sulfate AVINZA (A-MQD) on polysomnographic measures of sleep in a population of chronic osteoarthritic pain patients with sleep difficulties. DESIGN: Single-center, single-blind, placebo-lead-in, 30 mg or 60 mg. Patients' sleep and neurocognition were objectively measured at a sleep laboratory, and patients self-rated their pain, sleep, and other functions. PARTICIPANTS: Thirty-four participants (26 to 75 years old) complaining of sleep difficulties and chronic, stable pain secondary to hip or knee osteoarthritis. INTERVENTIONS: Participants had a screening visit on current pain medication and then, following a single-blind placebo run-in period, received 30 mg/d of A-MQD for six days. At day 6, doses for participants with incomplete pain relief on the Brief-Pain-Inventory (BPI) pain scale were increased to 60 mg/d. Treatment continued for another eight days at the new dose level (14 days for a subgroup at 60 mg/d). Sleep was objectively measured by all-night polysomnography (PSG) at screening while on the participants' current pain therapy, at baseline following a placebo run-in and at the end of treatment while on A-MQD. OUTCOME MEASURES: PSG parameters evaluated included Total-Sleep-Time (TST), Wake-timeafter-Sleep-Onset (WASO), Sleep-Efficiency (SE), Latency-to-Persistent Sleep (LPS), Latency-to-REM-sleep, the Number-of-Awakenings (NAW), the time spent in each stage of sleep, and REM-sleep-latency. Subjective evaluations included participants' estimations of sleep time and sleep quality, the Epworth-Sleepiness-Scale (ESS), the BPI, and participant acceptance of and relief due to current therapy. Assessments of neurocognitive function were also made. RESULTS: Sleep initiation and maintenance tended to improve with A-MQD as demonstrated by the increases in TST and SE and decreases in WASO and NAW as compared with placebo-baseline values. Sleep architecture was preserved by the study drug and some increases in stage 2 and 3/4 sleep were seen compared with placebo baseline. Subjective ratings of sleep quality and sleep time were significantly improved with treatment, as were BPI scores and ratings of medication acceptance and pain relief. A-MQD was generally well tolerated. CONCLUSIONS: A-MQD was an effective treatment for pain, and this study treatment was associated with improvement of both objective and subjective sleep parameters in participants with chronic osteoarthritic pain.
Subject(s)
Delayed-Action Preparations/therapeutic use , Morphine/therapeutic use , Osteoarthritis/complications , Pain/drug therapy , Sleep Wake Disorders/drug therapy , Sleep/drug effects , Administration, Oral , Adult , Aged , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/therapeutic use , Capsules , Chronic Disease , Delayed-Action Preparations/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Morphine/administration & dosage , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Pain/etiology , Pain/physiopathology , Pain Measurement , Pilot Projects , Polysomnography/methods , Quality of Life , Single-Blind Method , Sleep/physiology , Sleep Wake Disorders/etiology , Sleep Wake Disorders/physiopathology , Time FactorsABSTRACT
Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Benzopyrans/pharmacology , Benzylidene Compounds/pharmacology , Glucocorticoids/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Benzopyrans/chemistry , Benzopyrans/therapeutic use , Benzylidene Compounds/chemistry , Benzylidene Compounds/therapeutic use , Cell Line, Tumor , Gene Expression/drug effects , Glucocorticoids/chemistry , Glucocorticoids/therapeutic use , Ligands , Mice , Mice, Inbred Strains , Osteogenesis/drug effects , Rats , Receptors, Glucocorticoid/metabolismABSTRACT
The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.
Subject(s)
Anabolic Agents/chemical synthesis , Androgen Receptor Antagonists , Androgens , Bone Density Conservation Agents/chemical synthesis , Pyrrolidines/chemical synthesis , Quinolines/chemical synthesis , Quinolones/chemical synthesis , Administration, Oral , Anabolic Agents/pharmacokinetics , Anabolic Agents/pharmacology , Animals , Biological Availability , Bone Density Conservation Agents/pharmacokinetics , Bone Density Conservation Agents/pharmacology , Female , Humans , Hypogonadism/drug therapy , Hypogonadism/pathology , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Organ Size/drug effects , Osteoporosis, Postmenopausal/drug therapy , Prostate/drug effects , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Quinolines/pharmacokinetics , Quinolines/pharmacology , Quinolones/pharmacokinetics , Quinolones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzopyrans/chemical synthesis , Multiple Myeloma/drug therapy , Quinolines/chemical synthesis , Receptors, Glucocorticoid/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , Binding, Competitive , Dexamethasone/pharmacology , Humans , Mice , Mineralocorticoid Receptor Antagonists , Models, Molecular , Multiple Myeloma/pathology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Mineralocorticoid/agonists , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure-activity relationships for this series of compounds are presented.
Subject(s)
Chrysenes/pharmacology , Receptors, Glucocorticoid/drug effects , Chrysenes/chemical synthesis , Chrysenes/chemistry , Structure-Activity RelationshipABSTRACT
Acquired drug resistance is a major obstacle in cancer therapy. As for many other drugs, this is also the case for gemcitabine, a nucleoside analogue with activity against non-small cell lung cancer (NSCLC). Here, we evaluate the ability of bexarotene to modulate the acquisition and maintenance of gemcitabine resistance in Calu3 NSCLC models. In the prevention model, Calu3 cells treated repeatedly with gemcitabine alone gradually developed resistance. However, with inclusion of bexarotene, the cells remained chemosensitive. RNA analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in gemcitabine resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased, suggesting that resistance was due to gene amplification at the chr11 p15.5 locus. Analysis of genomic DNA confirmed that the rrm1 gene copy number was increased over 10-fold. Correspondingly, fluorescence in situ hybridization analysis of metaphase chromosomes showed an intrachromosomal amplification of the rrm1 locus. In the therapeutic model, bexarotene gradually resensitized Calu3-GemR cells to gemcitabine, reaching parental drug sensitivity after 10 treatment cycles. This was associated with a loss in rrm1 amplification. Corresponding with the in vitro data, xenograft tumors generated from the resistant cells did not respond to gemcitabine but were growth inhibited when bexarotene was added to the cytotoxic agent. The data indicate that bexarotene can resensitize gemcitabine-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have clinical utility in cancers where drug resistance by gene amplification is a major obstacle to successful therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Retinoid X Receptors/agonists , Tetrahydronaphthalenes/pharmacology , Animals , Bexarotene , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/pharmacology , Drug Resistance, Neoplasm , Drug Synergism , Female , Gene Amplification/drug effects , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Nude , Tetrahydronaphthalenes/administration & dosage , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
Subject(s)
Oxazines/chemical synthesis , Quinolones/chemical synthesis , Receptors, Androgen/drug effects , Anabolic Agents/chemical synthesis , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Androgens , Animals , Binding, Competitive , Cell Line, Tumor , Humans , Male , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/drug effects , Organ Size/drug effects , Oxazines/chemistry , Oxazines/pharmacology , Prostate/anatomy & histology , Prostate/drug effects , Quinolones/chemistry , Quinolones/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
PURPOSE: Bexarotene is a rexinoid (selective retinoid X receptor agonist) that affects proliferation, differentiation, and apoptosis in preclinical studies. The relationship between bexarotene levels and biomarker changes in tumor tissues has not been previously studied. EXPERIMENTAL DESIGN: BEAS-2B human bronchial epithelial (HBE) cells, retinoid-resistant BEAS-2B-R1 cells, A427, H226, and H358 lung cancer cells were treated with bexarotene. Proliferation and biomarker expression were assessed. In a proof-of-principle clinical trial, bexarotene tumor tissue levels and intratumoral pharmacodynamic effects were assessed in patients with stages I to II non-small cell lung cancer. Bexarotene (300 mg/m(2)/day) was administered p.o. for 7 to 9 days before resection. RESULTS: Bexarotene-induced dosage-dependent repression of growth, cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phospho-EGFR expression in BEAS-2B, BEAS-2B-R1, A427, and H358, but not H226 cells. Twelve patients were enrolled, and 10 were evaluable. Bexarotene treatment was well tolerated. There was nonlinear correlation between plasma and tumor bexarotene concentrations (r(2) = 0.77). Biomarker changes in tumors were observed: repression of cyclin D1, total EGFR and proliferation in one case; repression of cyclin D3, total and phospho-EGFR in another. The cases with multiple biomarker changes had high tumor bexarotene (107-159 ng/g). A single biomarker change was detected in one case with low tumor bexarotene. CONCLUSION: Bexarotene represses proliferation and biomarker expression in responsive, but not resistant HBE and lung cancer cells. Similar biomarker changes occur in lung tumors when therapeutic intratumoral bexarotene levels are achieved. This proof-of-principle trial approach is useful to uncover pharmacodynamic mechanisms in vivo and relate these to intratumoral pharmacokinetic effects.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Tetrahydronaphthalenes/therapeutic use , Bexarotene , Biomarkers, Tumor/analysis , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Humans , Lung Neoplasms/blood , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Pilot Projects , Postoperative Period , Premedication/methods , Tetrahydronaphthalenes/blood , Tetrahydronaphthalenes/pharmacokinetics , Tumor Cells, CulturedABSTRACT
This multicenter trial compared the efficacy, safety, and effect on quality of life and work limitation of once-daily extended-release morphine sulfate capsules (AVINZA, A-MQD) and twice-daily controlled-release oxycodone HCI tablets (OxyContin, O-ER) in subjects with chronic, moderate to severe low back pain. After randomization and a period of opioid dose titration, subjects (n=266) underwent an eight-week evaluation phase and an optionalf our-month extension phase (n=174 in extension phase). Subjects were assessed using the 12-item Short-Form Health Survey (SF-12) and the Work Limitations Questionnaire (WLQ). In both groups, significant improvements were observed in the SF-12 mean scores forp hysicalf unctioning (p < 0.001), role physical (p < 0.0001), bodilyp ain (p < 0.0001), physical summary (p < 0.001), and mental component summary (p < 0.005). At the end of the titration period, greater relative improvements from baseline were seen in the SF-12 section on physical components in the A-MQD group versus the O-ER group, with significant differences observed for physical functioning (p = 0.0374), role physical (p = 0.0341), bodily pain (p = 0.0001), andp hysical summary (p = 0.0022). In both groups, SF-12 mean scores improved significantly for mental health (p < 0.01), role emotional (p < 0.01), socialfunctioning (p < 0.0005), vitality (p < 0.005), and the mental component summary (p < 0.005), but no significant differences were noted between the two groups. Both groups reported improvement from baseline in WLQ physical demands scores, with no significant differences noted between the two groups. At the end of the evaluation phase, fewer subjects were unable to work due to illness or treatment in the A-MQD group than in the O-ER group (8.5 percent versus 19.4 percent, respectively; p = 0.0149). In conclusion, compared to twice-daily OxyContin, once-daily A VINZA resulted in significantly better and earlier improvement ofp hysicalf unction and ability to work.
Subject(s)
Analgesics, Opioid/administration & dosage , Low Back Pain/drug therapy , Morphine/administration & dosage , Oxycodone/administration & dosage , Adult , Aged , Chronic Disease , Delayed-Action Preparations , Health Surveys , Humans , Middle Aged , Quality of Life , Surveys and Questionnaires , Work Capacity EvaluationABSTRACT
A series of selective androgen receptor modulators (SARMs) with a wide spectrum of receptor modulating activities was developed based on optimization of the 4-substituted 6-bisalkylamino-2-quinolinones (3). Significance of the trifluoromethyl group on the side chains and its interactions with amino acid residues within the androgen receptor (AR) ligand binding domain are discussed. A representative analog (9) was tested orally in a rodent model of hypogonadism and demonstrated desirable tissue selectivity.
Subject(s)
Quinolines/chemistry , Quinolines/chemical synthesis , Receptors, Androgen/drug effects , Androgen Antagonists/chemical synthesis , Androgen Antagonists/pharmacology , Androgen Receptor Antagonists , Androgens , Animals , Binding, Competitive/drug effects , Dihydrotestosterone/antagonists & inhibitors , Dihydrotestosterone/pharmacology , Genitalia, Male/drug effects , Hypogonadism/drug therapy , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Molecular Conformation , Orchiectomy , Organ Size/drug effects , Organ Specificity , Prostate/drug effects , Rats , Structure-Activity Relationship , TransfectionABSTRACT
A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays.
Subject(s)
Quinolines/chemistry , Quinolines/pharmacology , Receptors, Androgen/drug effects , Androgen Antagonists/chemical synthesis , Androgen Antagonists/pharmacology , Androgen Receptor Antagonists , Androgens , Anilides/pharmacology , Animals , Cell Line , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Nitriles/pharmacology , Quinolines/chemical synthesis , Structure-Activity Relationship , Tosyl Compounds/pharmacology , TransfectionABSTRACT
A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids, suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.
Subject(s)
Aminoquinolines/pharmacology , Copulation/drug effects , Lumbar Vertebrae/drug effects , Muscle, Skeletal/drug effects , Prostate/drug effects , Quinolones/pharmacology , Administration, Oral , Aminoquinolines/chemical synthesis , Aminoquinolines/metabolism , Animals , Antineoplastic Agents, Hormonal/pharmacology , Biomechanical Phenomena , Cell Line, Tumor , Fluoxymesterone/pharmacology , Humans , Lumbar Vertebrae/physiology , Male , Orchiectomy , Osteosarcoma , Prostatic Neoplasms , Quinolones/chemical synthesis , Quinolones/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Androgen/metabolism , SpodopteraABSTRACT
The androgen receptor is a member of the extended family of nuclear receptors and is widely distributed throughout the body. Androgen therapy is used to compensate for low levels of the natural hormones testosterone (T) and dihydrotestosterone and consists of administration of T, prodrugs thereof, or synthetic androgens. However, currently available androgens have many drawbacks. We identified 6-dialkylamino-4-trifluoromethylquinolin-2(1H)-ones as orally available tissue-selective androgen receptor modulators.
Subject(s)
Aminoquinolines/chemical synthesis , Androgens/chemical synthesis , Quinolines/chemical synthesis , Quinolones/chemical synthesis , Receptors, Androgen/drug effects , Administration, Oral , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Androgens/chemistry , Androgens/pharmacology , Animals , Binding Sites , Binding, Competitive , Humans , In Vitro Techniques , Male , Models, Molecular , Orchiectomy , Organ Size , Pelvic Floor/anatomy & histology , Prostate/anatomy & histology , Prostate/drug effects , Quinolines/chemistry , Quinolines/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Rats , Receptors, Androgen/metabolism , Structure-Activity Relationship , TransfectionABSTRACT
This large, open-label, randomized, parallel-group, multicenter study compared two oral sustained-release opioids (SROs)--AVINZA (A-MQD), morphine sulfate extended-release capsules given once a day, and OxyContin (O-ER), oxycodone modified-release tablets given twice a day--in SRO-naive subjects ages 30 to 70 with chronic, moderate to severe low back pain. Of the 392 subjects enrolled and randomized, 266 (132 in the A-MQD group and 134 in the O-ER group) completed the opioid dose titration phase and entered an eight-week evaluation phase. During the evaluation phase, A-MQD achieved significantly better pain control than O-ER, as demonstrated by a greater decrease from baseline in pain scores obtained four times daily during weeks one, four, and eight (p = 0.002). The number of breakthrough-pain rescue medication doses adjusted for the number of patient days was significantly lower in the A-MQD group (p < 0.0001). Better pain control with A-MQD was achieved with a significantly lower daily opioid dose than with O-ER (mean 69.9 mg and 91 mg morphine equivalents, respectively; p = 0.0125). Quality of sleep was significantly better with A-MQD for the entire evaluation phase (p = 0.0026). The incidence and severity of elicited opioid side effects were similar in the two groups. This trial demonstrated that once-daily A-MQD provides consistent around-the-clock pain relief in patients with low back pain. In patients who completed opioid dose titration, A-MQD was significantly better than O-ER for reducing pain and improving sleep, while requiring a lower daily opioid dose.