Therapy For Small Cell Lung Cancer Research Articles

Capsaicin induces apoptosis in human small cell lung cancer via the TRPV pathway

Capsaicin, the spicy ingredient of chili peppers, is used to topically treat pain and inflammation associated with a variety of diseases. However, emerging evidence shows that it can induce apoptosis in different transformed cell types in vitro and in animal models. The present study examines the apoptotic activity of capsaicin in human small cell lung cancer (SCLC). Here we show that capsaicin induced apoptosis in a panel of human SCLC in a concentration‐dependent and time‐dependent manner. Most importantly, capsaicin caused 5–6 fold apoptosis in a panel of human SCLC cell lines, but did not affect normal human lung epithelial cells. The dietary administration of capsaicin decreased the growth of H69 and DMS53 human SCLC tumors xenotransplanted in nude mice. The apoptotic activity of capsaicin was independent of TRPV1, the known receptor for capsaicin. In contrast, depletion of TRPV6 by siRNA ablated the apoptotic activity of capsaicin. Our findings suggest that capsaicin may have potential applications as a novel agent for management and therapy of human SCLCs.

MG624, an α7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway

Small cell lung cancer (SCLC) demonstrates a strong etiological association with smoking. Although cigarette smoke is a mixture of about 4,000 compounds, nicotine is the addictive component of cigarette smoke. Several convergent studies have shown that nicotine promotes angiogenesis in lung cancers via the α7-nicotinic acetylcholine receptor (α7-nAChR) on endothelial cells. Therefore, we conjectured that α7-nAChR antagonists may attenuate nicotine-induced angiogenesis and be useful for the treatment of human SCLC. For the first time, our study explores the anti-angiogenic activity of MG624, a small-molecule α7-nAChR antagonist, in several experimental models of angiogenesis. We observed that MG624 potently suppressed the proliferation of primary human microvascular endothelial cells of the lung (HMEC-Ls). Furthermore, MG624 displayed robust anti-angiogenic activity in the Matrigel, rat aortic ring and rat retinal explant assays. The anti-angiogenic activity of MG624 was assessed by two in vivo models, namely the chicken chorioallantoic membrane model and the nude mice model. In both of these experimental models, MG624 inhibited angiogenesis of human SCLC tumors. Most importantly, the administration of MG624 was not associated with any toxic side effects, lethargy or discomfort in the mice. The anti-angiogenic activity of MG624 was mediated via the suppression of nicotine-induced FGF2 levels in HMEC-Ls. MG624 decreased nicotine-induced early growth response gene 1 (Egr-1) levels in HMEC-Ls, and reduced the levels of Egr-1 on the FGF2 promoter. Consequently, this process decreased FGF2 levels and angiogenesis. Our findings suggest that the anti-angiogenic effects of MG624 could be useful in anti-angiogenic therapy of human SCLCs.

Targeting the Hedgehog and Notch Signaling Pathways

Targeting the Hedgehog and Notch Signaling Pathways

HIF-1α effects on angiogenic potential in human small cell lung carcinoma.

BackgroundHypoxia-inducible factor-1 alpha (HIF-1α) maybe an important regulatory factor for angiogenesis of small cell lung cancer (SCLC). Our study aimed to investigate the effect of HIF-1α on angiogenic potential of SCLC including two points: One is the effect of HIF-1α on the angiogenesis of SCLC in vivo. The other is the regulation of angiogenic genes by HIF-1α in vitro and in vivo.MethodsIn vivo we used an alternative method to study the effect of HIF-1a on angiogenic potential of SCLC by buliding NCI-H446 cell transplantation tumor on the chick embryo chorioallantoic membrane (CAM) surface. In vitro we used microarray to screen out the angiogenic genes regulated by HIF-1a and tested their expression level in CAM transplantation tumor by RT-PCR and Western-blot analysis.ResultsIn vivo angiogenic response surrounding the SCLC transplantation tumors in chick embryo chorioallantoic membrane (CAM) was promoted after exogenous HIF-1α transduction (p < 0.05). In vitro the changes of angiogenic genes expression induced by HIF-1α in NCI-H446 cells were analyzed by cDNA microarray experiments. HIF-1α upregulated the expression of angiogenic genes VEGF-A, TNFAIP6, PDGFC, FN1, MMP28, MMP14 to 6.76-, 6.69-, 2.26-, 2.31-, 4.39-, 2.97- fold respectively and glycolytic genes GLUT1, GLUT2 to2.98-, 3.74- fold respectively. In addition, the expression of these angiogenic factors were also upregulated by HIF-1α in the transplantion tumors in CAM as RT-PCR and Western-blot analysis indicated.ConclusionsThese results indicated that HIF-1α may enhance the angiogenic potential of SCLC by regulating some angiogenic genes such as VEGF-A, MMP28 etc. Therefore, HIF-1α may be a potential target for the gene targeted therapy of SCLC.

A phase II study of second-line bendamustine in relapsed or refractory small cell lung cancer (SCLC).

e17505 Background: Bendamustine is an alkylating agent with a nitrogen mustard group and purine-like benzimidazole group. Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster W et al. J Tho Onc. 2007;2(4):312-6]. This study aims to examine the safety and efficacy of single agent bendamustine as 2nd or 3rd line therapy in patients (pts) with SCLC. Methods: This is an open-label, multicenter phase II trial. Eligible pts had previously treated SCLC, up to 2 prior regimens, PS 0-2, evaluable/measurable disease, adequate marrow, renal and hepatic function. Pts with stable treated brain metastases were allowed. Pts were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) up to 6 cycles and evaluated every 2 cycles. Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity. Results: 28 pts have enrolled to date (target accrual 60); 19 pts were evaluable for response; there were 7 PR, 7 SD and 5 PD. Median TTP was 2.5 months. At the time of analysis, 12 pts were alive. Median number of cycles given was 2. 5 pts required dose reductions due to AEs. Grade 3/4 AEs included neutropenia 14.3%, fatigue 10.7%, anemia and diarrhea 7.1% and less commonly, thrombocytopenia, nausea, infection, hyponatremia, pulmonary at 3.6%. Conclusions: These preliminary data indicate that single agent bendamustine appears to be well tolerated and effective in the second or third line setting for patients with SCLC. Accrual is ongoing.

Abstract 5411: Development of SCLC specific nanoparticle-mediated therapeutic gene delivery

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is a particularly aggressive form of lung cancer characterized by early metastatic behavior. Even with currently recommended therapy, the average survival of SCLC patients is less than 1 year. There is an urgent need for novel treatments. The majority (70-90%) of SCLC cases possess alterations in p53 and Rb. This relative genetic homogeneity makes SCLC an attractive context in which to develop and test novel gene therapy approaches. We have initiated studies using non-viral, poly-β amino acid ester (PBAE) nanoparticle delivery of gene therapy in SCLC. PBAE polymers possess numerous advantages over viral delivery systems such as structural diversity, cost effectiveness, low immunogenicity and higher stability. PBAEs encapsulate DNA to form biodegradable cationic nanoparticles and have been studied in a variety of cancer cell types and in primary endothelial cells. This is the first study of PBAEs in SCLC. A PBAE polymer library was screened in two SCLC lines using a luciferase-based high-throughput screen (HTS). Thirty-two of 112 polymers were further characterized in the H446 SCLC cell line using a CMV-GFP reporter construct and analyzed by qualitative (microscopy) and quantitative (flow cytometry) methods. This secondary screen revealed that the polymers had variable transfection efficiencies ranging from 8-55%. Four polymers, 446LG, 447LG, 456LG and 457 exhibited high transfection efficiencies (42-55%) in two SCLC cell lines, including one suspension line. Using PBAEs complexed with Cy5-labeled DNA, we were able to demonstrate that &amp;gt;90% cells bind and internalize the nanoparticles. We have initiated studies to better elucidate bottlenecks between nanoparticle uptake and gene expression. Additionally, preliminary studies in tumor-bearing athymic nude mice demonstrated gene uptake and expression via intratumoral injection of 457 and 446LG polymer/DNA complexes. Ongoing studies include further optimization of PBAEs for in vitro gene expression and systemic in vivo delivery. In parallel, we are performing genetic characterization of patient-derived primary SCLC xenografts to verify relevant gene targets. Taken together, our data supports further development of a non-viral PBAE-based gene delivery approach in SCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5411. doi:10.1158/1538-7445.AM2011-5411

Abstract 1729: Connecting Gli1 with chemoresistance in small cell lung cancer

Abstract Background. Small-cell lung cancer (SCLC) accounts for ∼15% of all lung cancers, and is the most aggressive form of lung cancer. Drug resistance to chemotherapeutics is particularly crippling in SCLC as there are limited treatment options. We previously examined gene expression in platinum-resistant SCLC cell lines, and reported aberrant expression of a subset of hedgehog pathway related genes, among which Gli1 was particularly significant. Gli1 is a known transcription factor that is involved with regulation of a number of key genes in cell fate determination and proliferation. In recent years, its role in oncogenesis and cancer progression has been studied. Herein, we test the hypothesis that increased Gli1 expression contributes to cisplatin and etoposide resistance in SCLC. Methods. Two SCLC cell lines, H69 and H526, were transduced with a Gli1 over-expressing (o/e) vector (Kasper et al, 2007) to create two lines expressing the gene: H69-Gli1 and H526-Gli1. Gli1 expression was verified by qRT-PCR. Cellular proliferation was measured over 96 hours. To study the drug dose response, Gli1 o/e and parental lines were treated with single-agent or combination dosing of cisplatin and etoposide (standard first-line SCLC therapy), and cell viability was assessed after 72 hours. Relative Gli1 expression was compared with cisplatin response in four additional SCLC cell lines (H146, H187, H345, H1688). To further understand aberrant cellular signaling in Gli1 o/e cells, gene expression analysis was performed on H69-Gli1 and H69 parental cells (2 replicates) using Agilent 44K expression arrays. Data was normalized and analyzed using Genespring software. Changes greater than 2 fold were considered significant. Results. Compared to parental cells, Gli1 expression was 11 fold and 149 fold higher in H69-Gli1 and H526-Gli1, respectively. Proliferation assays showed no significant differences in parental vs. Gli1 o/e cells. Drug dose response experiments showed at least a 1.5 fold shift in cisplatin resistance in H69-Gli1 compared to H69. The same trend was also observed in combination dosing of cisplatin and etoposide. H526-Gli1 showed no significant change in cisplatin resistance compared to H526. In the four additional SCLC lines a positive trend was observed where increased Gli1 expression correlated with increased cisplatin resistance. Gene expression analysis showed that there are over 1200 genes significantly differentially-expressed in H69-Gli1 cells as compared to parental cells. Conclusions. Gli1 over-expression leads to increased platinum resistance in SCLC cells. We are currently in the process of performing pathway analysis on the gene expression data to study the pathways affected by Gli1 over-expression in H69 cells, leading to increased platinum resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1729. doi:10.1158/1538-7445.AM2011-1729

Second-line therapy for small-cell lung cancer

Small-cell lung cancer (SCLC) recurs in the majority of patients, even though most patients respond to first-line therapy. Therefore second-line therapy is considered in almost all patients with SCLC in the course of disease. Efficacy of second-line chemotherapy is much lower than that of first-line treatment, but it can provide significant palliation and prolongation of survival for many patients. Patients receiving second-line therapy are divided into relapsed and refractory patients. Relapsed disease is defined as relapse or progression at least 3 months after the end of first-line therapy. All other situations, including a treatment-free interval <3 months or no response to first-line therapy, are termed refractory disease. The benefit from second-line chemotherapy is highest in patients with relapsed disease. Topotecan monotherapy improves survival and quality of life, as well as cancer-related symptoms in the second-line setting. Alternatively, doxorubicin-based combination therapy can be administered with a similar outcome but a slightly lower rate of symptom control. In refractory patients no standard therapy exists. Amrubicin, a novel anthracyline, showed promising activity in refractory and relapsed patients. Phase III trials are ongoing. Other agents with activity include irinotecan, paclitaxel, docetaxel, gemcitabine, bendamustine and vinorelbine.

A Role for IGF-1R–Targeted Therapies in Small-Cell Lung Cancer?

BackgroundSmall-cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. The insulin-like growth factor-1 receptor (IGF-1R) is an autocrine growth factor and an attractive therapeutic target in many solid tumors, but particularly in lung cancer. Patients and MethodsThis study examined tumor samples from 23 patients diagnosed with SCLC, 11 resected specimens and 12 nodal biopsies obtained by mediastinoscopy, for expression of IGF-1R using the monoclonal rabbit anti–IGF-1R (clone G11, Ventana Medical Systems, Tucson, AZ) and standard immunohistochemistry (IHC). ResultsAll 23 tumor samples expressed IGF-1R with a range of stain intensity from weak (1+) to strong (3+). Ten tumors had a score of 3+, 7 tumors 2+, and 6 tumors 1+. Patient survival data were available for all 23 patients. Two patients died < 30 days post biopsy, therefore, the intensity of anti–IGF-1R immunostaining for 21 patients was correlated to survival. Patients with 3+ immunostaining had a poorer prognosis (P = .003). The overall survival of patients who underwent surgical resection was significantly better (median survival not reached) than patients who were not resected (median survival, 7.4 months) (P = .006). ConclusionIGF-1R targeted therapies may have a role in the treatment of SCLC in combination with chemotherapy or as maintenance therapy. Further studies on the clinical benefit of targeting IGF-1R in SCLC are needed.

Radiation-induced sarcoma in bronchial stump after thoracic radiation therapy for small-cell lung cancer

We report a rare case of radiation-induced sarcoma (RIS) that arose in the right bronchial stump, 8 years after right pneumonectomy followed by adjuvant chemotherapy and thoracic radiotherapy for a localized small-cell lung cancer. The patient was treated in 2002 with 6 MV X-ray irradiation in a total dose of 60 Gy. Eight years after the end of radiotherapy, he presented with an undifferentiated high-grade pleomorphic sarcoma. Although an increased rate of soft tissue sarcoma has been reported after radiotherapy for some solid cancers or lymphomas, to our knowledge, this is the first report of RIS related to small-cell lung cancer.

Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy

Small-cell lung cancer (SCLC) is the most aggressive lung cancer subtype and lacks effective early detection methods and therapies. A number of rare paraneoplastic neurologic autoimmune diseases are strongly associated with SCLC. Most patients with such paraneoplastic syndromes harbor high titers of antibodies against neuronal proteins that are abnormally expressed in SCLC tumors. These autoantibodies may cross-react with the nervous system, possibly contributing to autoimmune disease development. Importantly, similar antibodies are present in many SCLC patients without autoimmune disease, albeit at lower titers. The timing of autoantibody development relative to cancer and the nature of the immune trigger remain to be elucidated. Here we review what is currently known about SCLC-associated autoantibodies, and describe a recently developed mouse model system of SCLC that appears to lend itself well to the study of the SCLC-associated immune response. We also discuss potential clinical applications for these autoantibodies, such as SCLC diagnosis, early detection, and therapy.

Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: A multi-institutional retrospective analysis

BackgroundPatients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy. Patients and methodsWe retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. ResultsThe median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months.The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy.A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors. ConclusionsThe outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy.

Small Cell Lung Cancer: Past, Present, and Future

Small cell lung cancer (SCLC) accounts for about 10% to 15% of all lung cancers. It is characterized by its rapid doubling time, high rate of dissemination, and increased sensitivity to chemotherapy and radiation. Although the incidence of SCLC has been steadily decreasing over time, it remains a serious public health problem given its aggressive clinical behavior and the lack of effective therapies. This review looks at the evolution of SCLC treatment and the standard treatments that are currently available, including platinum-based combination chemotherapy, hyperfractionated thoracic radiation, and prophylactic cranial irradiation. The development of novel therapies for SCLC has been lagging behind, but completed clinical trials and ongoing investigations are helping us define what will be the best therapeutic targets for this disease.

β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. Beta-lapachone (beta-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non-small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, beta-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. Beta-lap micelles produced by a film sonication technique were small ( approximately 30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t(1/2), approximately 28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable beta-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors.

Capsaicin Displays Anti-Proliferative Activity against Human Small Cell Lung Cancer in Cell Culture and Nude Mice Models via the E2F Pathway

BackgroundSmall cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo.Methodology/Principal FindingsBrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation.Conclusions/SignificanceOur findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs.

Abstract 4519: Small cell lung cancers lack expression of argininosuccinate synthase (ASS) and are sensitive to arginine deprivation using arginine deiminase-PEG20 (ADI-PEG20)

Abstract Various tumor types have been shown to lack expression of the enzyme argininosuccinate synthase (ASS) that is required for the synthesis of arginine and thus rely on exogenous sources for protein synthesis requirements. These tumors may be sensitive to arginine deprivation, and the absence of ASS expression may serve as a biomarker for this sensitivity. Arginine deiminase (ADI) is a microbial enzyme that has been shown to efficiently lower peripheral blood arginine. Its therapeutic efficacy has been previously explored in the treatment of melanoma and hepatocellular cancer in early phase clinical trials but clinical efficacy in these tumor types has been limited. However, other tumor types lacking ASS may be more sensitive to arginine depletion. We have investigated ASS expression in human small cell lung cancer (SCLC) tumor tissue by immunohistochemistry (IHC) and have so far found that about 43% (7/16) of SCLC tumors were negative for ASS. SCLC has a robust initial response to chemotherapy but the majority of cases relapse and there remain limited options in the treatment of refractory disease. Based on the IHC findings and the need for novel therapies in recurrent SCLC, we explored the effects of pegylated ADI (ADI-PEG20) mediated arginine deprivation in SCLC in vitro and in vivo. We screened a panel of 10 human SCLC cell lines for ASS mRNA and protein expression by Real Time PCR and Western blot analysis. Little or no ASS was observed in 50% (5 of 10) of the SCLC cell lines examined and this frequency is approximately equivalent to that found in the SCLC tumor tissues. In cell proliferation assays a clear correlation between expression of ASS and sensitivity to ADI-PEG20 was detected. Biochemical analysis of the mechanism of ADI-PEG20 induced cell death in ADI sensitive cell lines revealed induction of autophagy and cell death through caspase independent mechanisms. Assessment of ADI-PEG20 activity in vivo using mice bearing SCLC xenografts demonstrated that ADI-PEG20 treatment of ASS negative SCLC xenografts caused significant and dose dependent inhibition of tumor growth, while no effect was observed with placebo controls. These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this treatment in patients with ASS negative SCLC by IHC has been initiated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4519.

Targeted Cytosine Deaminase-Uracil Phosphoribosyl Transferase Suicide Gene Therapy Induces Small Cell Lung Cancer–Specific Cytotoxicity and Tumor Growth Delay

Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the nonviral nanoparticle DOTAP/cholesterol for transgene delivery. INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir. The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared with control-treated xenografts. The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo.

Capsaicin: a potential therapeutic agent for human small cell lung cancer

Capsaicin the major active ingredient of chili peppers can induce apoptosis in multiple human cancer cell lines in cell culture and animal models. The present study examines the anti‐neoplastic activity of capsaicin in human small cell lung cancer (SCLC). SCLC is characterized by rapid progression, early metastasis and low survival rates. Our study showed that capsaicin induced 5–6 fold increase in apoptosis in multiple human SCLC cell lines. Most interestingly, the apoptotic activity of capsaicin was only displayed in SCLC cells and not in normal human lung epithelial cells. Capsaicin also suppressed the invasion of human SCLC cells as determined by Boyden Chamber assays. The dietary administration of capsaicin decreased the growth of human SCLC tumors xenotransplanted in nude mice. The growth‐inhibitory activity of capsaicin was independent of TRPV1, which is known to be the classical receptor for capsaicin. In contrast, the growth‐inhibitory activity of capsaicin requires the TRPV6 receptor, and depletion of TRPV6 by siRNA ablated the growth‐inhibitory activity of capsaicin. Our findings suggest that capsaicin may have potential applications as a novel agent for management and therapy of human SCLCs. Funding for our study was supported by a COBRE Pilot Grant, CDDC Pilot Grant, an MU‐ADVANCE Fellowship, and the Flight Attendant Medical Research Institute YCSA Grant.

An update on small cell lung cancer therapy

An update on small cell lung cancer therapy

Evaluation of Circulating Tumor Cells and Serological Cell Death Biomarkers in Small Cell Lung Cancer Patients Undergoing Chemotherapy

Serological cell death biomarkers and circulating tumor cells (CTCs) have potential uses as tools for pharmacodynamic blood-based assays and their subsequent application to early clinical trials. In this study, we evaluated both the expression and clinical significance of CTCs and serological cell death biomarkers in patients with small cell lung cancer. Blood samples from 88 patients were assayed using enzyme-linked immunosorbent assays for various cytokeratin 18 products (eg, M65, cell death, M30, and apoptosis) as well as nucleosomal DNA. CTCs (per 7.5 ml of blood) were quantified using Veridex CellSearch technology. Before therapeutic treatment, cell death biomarkers were elevated in patients compared with controls. CTCs were detected in 86% of patients; additionally, CD56 was detectable in CTCs, confirming their neoplastic origin. M30 levels correlated with the percentage of apoptotic CTCs. M30, M65, lactate dehydrogenase, and CTC number were prognostic for patient survival as determined by univariate analysis. Using multivariate analysis, both lactate dehydrogenase and M65 levels remained significant. CTC number fell following chemotherapy, whereas levels of serological cell death biomarkers peaked at 48 hours and fell by day 22, mirroring the tumor response. A 48-hour rise in nucleosomal DNA and M30 levels was associated with early response and severe toxicity, respectively. Our results provide a rationale to include the use of serological biomarkers and CTCs in early clinical trials of new agents for small cell lung cancer.