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Biomedical subjects

Konstantin H Dragnev

Publications and source records attributed to Konstantin H Dragnev.

17 recordsLinked to original sources
PubMed2006

Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing.

The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.

Base Sequence↗
PubMed2006

Acute monocular blindness resulting from transformation of von Recklinghausen's neurofibromatosis to malignant melanocytic schwannomas.

A 59-year-old male was transferred to our facility after initial workup for left eye blindness revealed multiple brain lesions. The patient presented with scant pedunculated skin lesions on his neck and arms, axillary freckling and bilateral subcutaneous ankle nodules suggestive of neurofibromatosis type 1 (NF-1). Neurological examination revealed left-sided blindness, diminished pupillary response to light, incomplete eyelid closure and facial droop. A CT series of the chest/abdomen/pelvis demonstrated several lesions in the lungs, liver and left kidney. CT-guided biopsy of the renal lesion was "consistent with metastatic melanoma" based on the presence of malignant cell staining for the melanocyte differentiation antigen MART-1, as well as the calcium binding protein S-100. A dermatology consultant confirmed neurofibromas and a café au lait macule. No dysplastic nevi or primary melanoma were identified. An ophthalmology consultant noted gray choroidal lesions on fundoscopic examination thought to be metastatic disease of unknown primary. Despite treatment with whole brain irradiation and intravenous steroids, the patient died on hospital day 10. A full autopsy showed diffuse neurofibromas and café au lait macules consistent with NF-1 and malignant melanocytic schwannomas with multiple metastases.

Blindness↗
PubMed2005

Bexarotene and erlotinib for aerodigestive tract cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity. PATIENTS AND METHODS: In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non-small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective. RESULTS: Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%. CONCLUSION: The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m2/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.

Aged↗
PubMed2005

A novel retinoic acid receptor beta isoform and retinoid resistance in lung carcinogenesis.

BACKGROUND: We previously reported that all-trans-retinoic acid (RA) treatment can prevent in vitro transformation of immortalized human bronchial epithelial (HBE) cells. METHODS: To determine whether methylation inhibits RARbeta expression in HBE cells, we used sodium bisulfite sequencing to compare RARbeta P2 promoter methylation patterns in RA-sensitive (BEAS-2B) and RA-resistant (BEAS-2B-R1) HBE cells. Immunoblotting was used to assess induction of the RARbeta, placental transforming growth factor beta (PTGF-beta), Fos-related antigen 1 (Fra-1), and transglutaminase II (TGase II) proteins by RA following treatment with azacitidine, a DNA demethylating agent. The expression, transcriptional activity, and growth suppressive activity of RARbeta1', a novel RAR isoform, were evaluated in lung cancer cells transfected with RARbeta1', and expression was also studied in paired normal lung tissues and lung tumors. All statistical tests were two-sided. RESULTS: Hypermethylation was observed in the 3' region of the RARbeta P2 promoter of BEAS-2B-R1 but not BEAS-2B cells. Azacitidine treatment of BEAS-2B-R1 cells restored RA-inducible RARbeta2 and PTGF-beta expression but not that of RARbeta1', Fra-1, or TGase II. RARbeta1' expression was repressed in RA-resistant BEAS-2B-R1 cells and in lung cancers, compared with adjacent normal lung tissues. BEAS-2B-R1 cells transiently transfected with RARbeta1' had increased RA-dependent activation of a retinoic acid receptor element (RARE)-containing reporter plasmid compared with vector control (mean = 3.2, 95% confidence interval [CI] = 3.1 to 3.3 versus mean = 1.4, 95% CI = 1.3 to 1.5; P<.001). In H358 lung cancer cells transiently transfected with RARbeta1', RA treatment restored target gene expression compared with that in vector-transfected cells and suppressed cell growth compared with that in untreated cells (4 microM; treated mean = 0.49 versus untreated mean = 1.0, difference = 0.51, 95% CI = 0.35 to 0.67, P = .003; 8 microM: treated mean = 0.50 versus untreated mean = 1.0, difference = 0.50, 95% CI = 0.26 to 0.74, P = .015). CONCLUSION: Restoration of RARbeta1' expression may overcome retinoid resistance in lung carcinogenesis.

Antimetabolites, Antineoplastic↗
PubMed2005

Docetaxel in the treatment of esophageal cancer.

Esophageal cancer is the ninth most common malignancy in the world and the seventh leading cause of death in American men. Because symptoms are often intermittent and vague, patients typically present at an advanced stage, with limited survival. In operable patients, standard care includes surgery with or without adjuvant chemotherapy and radiotherapy; chemotherapy and radiotherapy is the standard care for inoperable disease. Docetaxel, a taxane that promotes polymerization of tubules and inhibits depolymerization of microtubules, has shown in vitro and in vivo antitumor effects on human gastric cell lines and gastric cancer xenografts. These antitumor effects have led to the evaluation of docetaxel as a single agent and in combination with other agents and modalities in patients with esophageal cancer. Results of relevant trials are reviewed herein.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Emerging role of rexinoids in non-small cell lung cancer: focus on bexarotene.

Although the introduction of third-generation antineoplastic agents in the treatment of non-small cell lung cancer has led to modest improvements in overall patient survival, lung cancer continues to be the leading cause of cancer-related death worldwide, and improved therapies are needed. Retinoids play a critical role in the regulation of cell division, growth, differentiation, and proliferation, and they represent an exciting new avenue for targeted therapy. Several synthetic retinoids that bind to retinoic acid receptors are currently being investigated in a variety of tumor types. However, many of these agents have been associated with cheilitis, skin reactions, severe headache, and hypertriglyceridemia. Synthetic agents that bind specifically to retinoid X receptors are called rexinoids. Bexarotene (Targretin; Ligand Pharmaceuticals; San Diego, CA; http://www.ligand.com) is a novel, multitargeted synthetic rexinoid that is currently being investigated in the treatment of non-small cell lung cancer. Phase I and II studies have demonstrated that bexarotene is safe and well tolerated in this patient population either alone or in combination with chemotherapeutic agents. Patients treated with bexarotene experience manageable adverse events at reduced levels compared with retinoic acid receptor-specific retinoids. Bexarotene in combination with chemotherapeutic agents has demonstrated an encouraging median survival for patients with advanced non-small cell lung cancer compared with historical results with combination chemotherapy alone. Two phase III trials are currently under way to fully characterize the role of bexarotene in the treatment of this disease. The purpose of this review is to explore the rationale for rexinoids in the treatment of malignancies and to discuss the clinical profile of bexarotene in the treatment of non-small cell lung cancer.

Anticarcinogenic Agents↗
PubMed2005

Nonclassical retinoids and lung carcinogenesis.

The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert antiproliferative, differentiation-inducing, proapoptotic, and other biologic effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal biologic effects. Agents that specifically activate the nuclear retinoid X receptors (RXRs) are known as rexinoids. Rexinoid growth suppression of human bronchial epithelial cells was linked to triggering of G1 cell cycle arrest, concomitant growth suppression, and a decrease in expression of G1 cyclins through activation of a proteasome-dependent degradation pathway. Clinical studies have demonstrated prolonged survival of subsets of patients with non-small-cell lung cancer (NSCLC) treated with rexinoids as single agents or as part of combination regimens. The critical role of RXR in downstream signaling makes rexinoids especially attractive agents to consider in combination therapy. There is encouraging evidence for therapeutic benefit of combination regimens of rexinoids with other targeted agents, such as epidermal growth factor receptor inhibitors, and with chemotherapy. Results from randomized phase III clinical trials in NSCLC will ultimately determine the impact for rexinoid-based therapy or chemoprevention for lung cancer.

Anticarcinogenic Agents↗
PubMed2004

Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are active in cancer therapy. Mechanisms engaged during these clinical responses need to be determined. We reported previously that epidermal growth factor stimulation markedly increased cyclin D1 protein expression in human bronchial epithelial (HBE) cells, and this was opposed by chemoprevention with all-trans-retinoic acid. The current study sought to determine whether the EGFR TKI erlotinib repressed cyclin D1 protein expression in immortalized HBE cells, lung cancer cell lines, and clinical aerodigestive tract cancers. EXPERIMENTAL DESIGN: The BEAS-2B immortalized HBE cell line was exposed to varying concentrations of erlotinib, and effects on proliferation, cell cycle distribution, G1 cyclin expression, and cyclin D1 reporter activity were measured. Non-small-cell lung cancer cell lines were also evaluated for changes in proliferation and cyclin protein expression after erlotinib treatments. A proof of principle clinical trial was conducted. During this study, patients underwent a 9-day course of erlotinib treatment. Pretreatment and posttreatment tumor biopsies were obtained, and changes in candidate biomarkers were determined by immunostaining. Plasma pharmacokinetics and tumor tissue erlotinib concentrations were measured. RESULTS: Erlotinib, at clinically achievable dosages, repressed BEAS-2B cell growth, triggered G1 arrest, and preferentially reduced cyclin D1 protein expression and transcriptional activation. Erlotinib also preferentially repressed proliferation and cyclin D1 protein expression in responsive, but not resistant, non-small-cell lung cancer cell lines. This occurred in the presence of wild-type EGFR sequence at exons 18, 19, and 21. Five patients were enrolled onto an erlotinib proof of principle clinical trial, and four cases were evaluable. Pharmacokinetic studies established therapeutic erlotinib plasma levels in all patients, but tissue levels exceeding 2 micromol/L were detected in only two cases. Notably, these cases had pathological evidence of response (necrosis) in posttreatment biopsies as compared with pretreatment biopsies. In these cases, marked repression of cyclin D1 and the proliferation marker Ki-67 was detected by immunohistochemical assays. Cases without pathological response to erlotinib did not exhibit changes in cyclin D1 or Ki-67 immunohistochemical expression and had much lower erlotinib tissue levels than did responding cases. CONCLUSIONS: Taken together, these in vitro and in vivo findings provide direct evidence for repression of cyclin D1 protein as a surrogate marker of response in aerodigestive tract cancers to erlotinib treatment. These findings also provide a rationale for combining an EGFR TKI with an agent that would cooperatively repress cyclin D1 expression in clinical trials for aerodigestive tract cancer therapy or chemoprevention.

Biomarkers, Tumor↗
PubMed2004

Microarray analyses uncover UBE1L as a candidate target gene for lung cancer chemoprevention.

Retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and chemoprevention. We reported previously that all-trans-retinoic acid (RA) treatment prevented carcinogen-induced transformation of immortalized human bronchial epithelial (HBE) cells. To identify cancer chemopreventive mechanisms, immortalized (BEAS-2B), carcinogen-transformed (BEAS-2B(NNK)), and RA-chemoprevented (BEAS-2B(NNK/RA)) HBE cells were used to conduct microarray analyses independently. Species increased in chemoprevented as compared with immortalized HBE cells (group I) and those augmented in chemoprevented as compared with transformed HBE cells (group II) included known RA-target genes as well as previously unrecognized RA-target genes in HBE cells. Unexpectedly, both groups were also enriched for interferon-stimulated genes. One interferon-stimulated gene of particular interest was UBE1L, the ubiquitin-activating enzyme E1-like protein. UBE1L expression was also induced after prolonged RA-treatment of immortalized HBE cells. UBE1L mRNA was shown previously as repressed in certain lung cancer cell lines, directly implicating UBE1L in lung carcinogenesis. Notably, UBE1L immunoblot expression was reduced in a subset of malignant as compared with adjacent normal lung tissues that were examined. Immunohistochemical analyses were performed using a new assay developed to detect this species using rabbit polyclonal anti-UBE1L antibodies independently raised against the amino- or carboxyl-termini of UBE1L. Studies done on paraffin-embedded and fixed tissues revealed abundant UBE1L, but low levels of cyclin D1 expression in the normal human bronchial epithelium, indicating an inverse relationship existed between these species. To study this further, cotransfection into HBE cells of wild-type or mutant UBE1L species was accomplished. In a dose-dependent manner, wild-type but not mutant UBE1L species repressed cyclin D1 expression. This implicated UBE1L in a retinoid chemoprevention mechanism involving cyclin D1 repression described previously. Taken together, these findings directly implicate UBE1L as a candidate-pharmacologic target for lung cancer chemoprevention. These findings also provide a mechanistic basis for the tumor suppressive effects of UBE1L through cyclin D1 repression.

Anticarcinogenic Agents↗
PubMed2004

Specific chemopreventive agents trigger proteasomal degradation of G1 cyclins: implications for combination therapy.

PURPOSE: There is a need to identify cancer chemoprevention mechanisms. We reported previously that all-trans-retinoic acid (RA) prevented carcinogenic transformation of BEAS-2B immortalized human bronchial epithelial cells by causing G(1) arrest, permitting repair of genomic DNA damage. G(1) arrest was triggered by cyclin D1 proteolysis via ubiquitin-dependent degradation. This study investigated which chemopreventive agents activated this degradation program and whether cyclin E was also degraded. EXPERIMENTAL DESIGN: This study examined whether: (a) cyclin E protein was affected by RA treatment; (b) cyclin degradation occurred in derived BEAS-2B-R1 cells that were partially resistant to RA; and (c) other candidate chemopreventive agents caused cyclin degradation. RESULTS: RA treatment triggered degradation of cyclin E protein, and ALLN, a proteasomal inhibitor, inhibited this degradation. Induction of the retinoic acid receptor beta, growth suppression, and cyclin degradation were each inhibited in BEAS-2B-R1 cells. Transfection experiments in BEAS-2B cells indicated that RA treatment repressed expression of wild-type cyclin D1 and cyclin E, but ALLN inhibited this degradation. Mutation of threonine 286 stabilized transfected cyclin D1, and mutations of threonines 62 and 380 stabilized transfected cyclin E, despite RA treatment. Specific chemopreventive agents triggered cyclin degradation. Nonclassical retinoids (fenretinide and retinoid X receptor agonists) and a synthetic triterpenoid (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) each suppressed BEAS-2B growth and activated this degradation program. However, a vitamin D3 analog (RO-24-5531), a cyclooxygenase inhibitor (indomethacin), and a peroxisome proliferator-activated receptor gamma agonist (rosiglitazone) each suppressed BEAS-2B growth, but did not cause cyclin degradation. BEAS-2B-R1 cells remained responsive to nonclassical retinoids and to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid. CONCLUSIONS: Specific chemopreventive agents activate cyclin proteolysis. Yet, broad resistance did not occur after acquired resistance to a single agent. This provides a therapeutic rationale for combination chemoprevention with agents activating non-cross-resistant pathways.

Anticarcinogenic Agents↗
PubMed2003

Microarray analysis uncovers retinoid targets in human bronchial epithelial cells.

Retinoids, the natural and synthetic derivatives of vitamin A, have a role in cancer treatment and prevention. There is a need to reveal mechanisms that account for retinoid response or resistance. This study identified candidate all-trans-retinoic acid (RA) target genes linked to growth suppression in BEAS-2B human bronchial epithelial cells. Microarray analyses were performed using Affymetrix arrays. A total of 11 RA-induced species were validated by reverse transcription polymerase chain reaction (RT-PCR), Western or Northern analyses. Three of these species were novel candidate RA-target genes in human bronchial epithelial cells. These included: placental bone morphogenetic protein (PLAB), polyamine oxidase isoform 1 (PAOh1) and E74-like factor 3 (ELF3). Expression patterns were studied in RA-resistant BEAS-2B-R1 cells. In BEAS-2B-R1 cells, RA dysregulated the expression of the putative lymphocyte G0/G1 switch gene (G0S2), heme oxygenase 1 (HMOX1), tumor necrosis factor-alpha-induced protein 2 (TNFAIP2), inhibitor of DNA binding 1(Id1), fos-like antigen 1 (FOSL1), transglutaminase 2 (TGM2), asparagine synthetase (ASNS), PLAB, PAOh1 and ELF3, while prominent induction of insulin-like growth-factor-binding protein 6 (IGFBP6) still occurred. In summary, this study identified 11 candidate RA-target genes in human bronchial epithelial cells including three novel species. Expression studies in BEAS-2B-R1 cells indicated that several were directly implicated in RA signaling, since their aberrant expression was linked to RA resistance of human bronchial epithelial cells.

Blotting, Northern↗
PubMed2003

Cyclin D1 as a target for chemoprevention.

Lung cancer is the leading cause of cancer mortality. Chemoprevention is an attractive strategy to combat this major public health problem. Pre-clinical and clinical studies have identified diverse candidate chemopreventive agents that affect cellular proliferation, differentiation, apoptosis and tumor angiogenesis, among other pathways. These pharmacological agents are undergoing testing through use of pre-clinical models and clinical trials. These studies have uncovered cyclin D1 as a chemoprevention target and a surrogate marker of chemopreventive response in the lung. Chemoprevention of tobacco-carcinogen transformed human bronchial epithelial (HBE) cells appears to be due at least partly to degradation of cyclin D1. These studies of cultured HBE cells were extended to the in vivo setting by examination of preneoplastic bronchial lesions that established the frequent aberrant expression of cyclin D1 in lung carcinogenesis. Certain retinoids, natural and synthetic derivatives of vitamin A, repress cyclin D1, but activation of the epidermal growth factor receptor (EGFR) induces cyclin D1. Retinoids and specific chemopreventive agents can activate the proteasome-dependent degradation of cyclin D1 and also repress EGFR expression, thereby reducing cyclin D1 levels. These actions oppose the mitogenic effects of cyclin D1. This is hypothesized to trigger G1 arrest and thereby permit repair of carcinogenic damage of genomic DNA. These and other pre-clinical and clinical studies that will be reviewed here indicate that cyclin D1 and perhaps other cyclins are attractive pharmacological targets for lung cancer chemoprevention.

Cell Transformation, Neoplastic↗
PubMed2003

Lung cancer prevention: the guidelines.

Lung carcinogenesis is a chronic and multi-step process resulting in malignant lung tumors. This progression from normal to neoplastic pulmonary cells or tissues could be arrested or reversed through pharmacologic treatments, which are known as cancer chemoprevention. These therapeutic interventions should reduce or avoid the clinical consequences of lung cancer by treating early neoplastic lesions before the development of clinically evident signs or symptoms of malignancy. Preclinical, clinical, and epidemiologic findings relating to different classes of candidate chemopreventive agents provide strong support for lung cancer prevention as an attractive therapeutic strategy. Smoking prevention and smoking cessation represent an essential approach to reduce the societal impact of tobacco carcinogenesis. However, even if all the goals of the national antismoking efforts were met, there still would be a large population of former smokers who would be at increased risk for lung cancers. Lung cancer also can occur in those persons who never have smoked. This article focuses on what is now known about pharmacologic strategies for lung cancer prevention. Randomized clinical trials using beta-carotene, retinol, isotretinoin or N-acetyl-cysteine did not show benefit for primary and tertiary lung cancer prevention. There is also evidence that the use of beta-carotene and isotretinoin for lung cancer chemoprevention in high-risk individuals may increase the risk for lung cancer, especially in individuals who continue to smoke. There is a need for relevant in vitro models to identify pathways that activate chemopreventive effects in the lung. An improved understanding of cancer prevention mechanisms should aid in the design of clinical trials and in the validation of candidate chemopreventive targets as well as the discovery of new targets. Until such studies are completed, no agent or combination of agents should be used for lung cancer prevention outside of a clinical trial.

Anticarcinogenic Agents↗
PubMed2002

The role of docetaxel in nonplatinum-based combination chemotherapy for non-small-cell lung cancer.

A number of newer chemotherapeutic agents including docetaxel, gemcitabine, irinotecan, and vinorelbine have demonstrated substantial activity in the treatment of non-small-cell lung cancer (NSCLC). Their palliative role as single agents and in combination with platinum has been well defined in NSCLC. More recently, combining these agents without platinum has been the primary objective of numerous worldwide clinical trials. Two of these docetaxel/nonplatinum-based combinations have demonstrated comparable activity to platinum-based regimens in randomized trials. While platinum-based chemotherapy remains an important therapy for treatment of NSCLC, nonplatinum combinations may be a reasonable alternative for patients. These docetaxel/nonplatinum combinations warrant further evaluation in randomized trials to define their optimal role as standard therapy for NSCLC.

Journal Article↗
PubMed2002

Evidence for the epidermal growth factor receptor as a target for lung cancer prevention.

PURPOSE: There is a need to identify lung cancer prevention mechanisms. All-trans-retinoic acid (RA) was reported previously to inhibit N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) carcinogenic transformation of BEAS-2B human bronchial epithelial cells (J. Langenfeld et al., Oncogene, 13: 1983-1990, 1996). This study was undertaken to identify pathways targeted during this chemoprevention. EXPERIMENTAL DESIGN: Because epidermal growth factor receptor (EGFR) overexpression is frequent in non-small cell lung cancers (NSCLC) and bronchial preneoplasia, BEAS-2B cells, carcinogen-transformed BEAS-2B(NNK) cells, and retinoid chemoprevented BEAS-2B(NNK RA) cells were each examined for EGFR expression. Whether RA treatment regulated directly EGFR expression or reporter plasmid activity was studied. RA effects on epidermal growth factor (EGF) induction of EGFR-phosphotyrosine levels, cyclin D1 expression and mitogenesis were examined in BEAS-2B cells. RESULTS: Findings reveal that NNK-mediated transformation of BEAS-2B cells increased EGFR expression. RA treatment repressed EGFR expression and reporter plasmid activity in these cells. This treatment reduced EGF-dependent mitogenesis as well as EGFR-associated phosphotyrosine levels and cyclin D1 expression. These findings extend prior work by highlighting EGFR as a chemoprevention target in the lung. Notably, RA treatment prevented transformation as well as outgrowth of EGFR overexpressing bronchial epithelial cells, despite NNK exposure. After acute NNK exposure, p53-induced species that appear after DNA damage or oxidative stress were evident before an observed increase in EGFR expression. CONCLUSIONS: These findings indicate how effective chemoprevention prevents carcinogenic transformation of bronchial epithelial cells when repair of genomic damage does not select against EGFR overexpressing cells. This implicates EGFR as a chemoprevention target in the carcinogen-exposed bronchial epithelium.

Antineoplastic Agents↗
PubMedDate not supplied

Retinoid targets in cancer therapy and chemoprevention.

The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert anti-proliferative, differentiation-inducing, pro-apoptotic and other biological effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal retinoid biological effects. Direct retinoid targets contain retinoid responsive elements in their promoters, are directly regulated by retinoids and reproduce retinoid biological effects once introduced into a responsive cell context. Through studies conducted in in vitro models, a proteolytic mechanism was linked to retinoid induced tumor cell differentiation and chemopreventive effects. Retinoid treatments can activate the proteasome-dependent degradation pathway. In acute promyelocytic leukemia (APL), all-trans-retinoic acid (RA) can also trigger degradation of the oncogenic protein, PML-RARalpha. Microarray analysis revealed involvement of an E1-like ubiquitin-activating enzyme, UBE1L, in this induction. Retinoid chemopreventive activity in human bronchial epithelial cells was linked to triggering of G(1) cell cycle arrest, concomitant growth suppression, and a decline in expression of G(1) cyclins. This can engage proteasome-dependent cyclin degradation, causing G(1) arrest and this permits repair of genomic DNA damage. The epidermal growth factor receptor (EGFR) was also identified as a retinoid target. Retinoids exert diverse biological effects. Different retinoid target genes likely trigger distinct effects. Identification of target genes is the next step towards a molecular understanding of mechanisms of retinoid response or resistance in cancer therapy and chemoprevention.

Animals↗