Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The great majority of cancer patients can initially be rendered free of detectable disease by surgery and/or chemotherapy. Adjuvant chemotherapy or radiation therapy are generally only minimally beneficial, so there is real need for additional methods of eliminating residual circulating cancer cells and micrometastases. This is the ideal setting for treatment with a cancer vaccine. The immune response induced is critically dependent on the antigenic epitope and vaccine design. For antibody induction there is one best vaccine design, conjugation of the antigen to an immunogenic protein such as KLH and the use of a potent adjuvant such as the saponins QS-21 and GPI-0100. This approach alone induced strong antibody responses against the glycolipids GM2, fucosyl GM1 and globo H and the mucin backbone MUC1, and cancer cells expressing these antigens. Other antigens required additional modifications to augment relevant immunogenicity. GD2 and GD3 lactones and N-propionylated polysialic acid were significantly more effective at inducing antibodies against tumor cells than the unmodified antigens. Tn, sTn and TF trimers (clusters) were significantly more effective than the monomers at inducing antibodies reactive with the cancer cell surface. The optimal approach for Le(Y), KSA, PSMA, and CA125 (MUC16) remains to be determined. Antibodies are ideally suited for eradicating pathogens from the bloodstream and from early tissue invasion. Passively administered and vaccine induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models, so antibody-inducing vaccines offer real promise in the adjuvant setting. Polyvalent vaccines will probably be required due to tumor cell heterogeneity, heterogeneity of the human immune response and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Over the next several years, Phase II clinical trials designed to determine the clinical impact of polyvalent conjugate vaccines will be initiated in the adjuvant setting in patients with SCLC and several epithelial cancers.
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PMID:Antibody inducing polyvalent cancer vaccines. 1621 70

Surgical resection remains a definitive treatment for prostate cancer. Yet, prostate cancer surgery is performed without image guidance for tumor margin, extension beyond the capsule and lymph node positivity, and without verification of other occult metastases in the surgical field. Recently, several imaging systems have been described that exploit near-infrared (NIR) fluorescent light for sensitive, real-time detection of disease pathology intraoperatively. In this study, we describe a high-affinity (9 nM), single nucleophile-containing, small molecule specific for the active site of the enzyme PSMA. We demonstrate production of a tetra-sulfonated heptamethine indocyanine NIR fluorescent derivative of this molecule using a high-yield LC/MS purification strategy. Interestingly, NIR fluorophore conjugation improves affinity over 20-fold, and we provide mechanistic insight into this observation. We describe the preparative production of enzymatically active PSMA using a baculovirus expression system and an adenovirus that co-expresses PSMA and GFP. We demonstrate sensitive and specific in vitro imaging of endogenous and ectopically expressed PSMA in human cells and in vivo imaging of xenograft tumors. We also discuss chemical strategies for improving performance even further. Taken together, this study describes nearly complete preclinical development of an optically based small-molecule contrast agent for image-guided surgery.
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PMID:High-affinity near-infrared fluorescent small-molecule contrast agents for in vivo imaging of prostate-specific membrane antigen. 1628 7

We have utilized a novel polyethylenimine (PEI)/DNA-betagal vector to investigate the specificity and efficiency of immuno-targeting prostate-specific membrane antigen (PSMA). Coupling of the PSMA-specific monoclonal antibody, J591, to the vector was facilitated via the high-affinity interaction between phenyl(di)boronic acid and salicylhydroxamic acid molecules. Highly efficient gene delivery by this prostate cancer (PCA)-targeted J591/polyethylene glycol (PEG)/PEI/DNA-betagal vector was demonstrated in PSMA-positive cells relative to controls, resulting in significant growth inhibition in vitro when the J591/PEG/PEI/DNA-p53 was used. Competition with free antibody resulted in about 90% reduction in both J591 internalization and betagal gene delivery, indicating specificity for PSMA-positive cells. More importantly, testing the efficiency of the J591/PEG/PEI/DNA-betagal targeting vector in an orthotopic PCA model in nude mice resulted in up to a 20-fold increase in gene delivery over the untargeted vector controls. The in vivo organ distribution profile also revealed betagal expression predominantly in the tumor, which was more than 1 log higher than the next highest level of expression in the lung. Furthermore, with the targeted vector containing the gene for yellow fluorescent protein or biotinylated J591, we further demonstrate in vivo that vector-mediated gene delivery is specific for both tumor cells and tumor-associated neovasculature in PSMA-positive tumors. These results suggest the potential for further optimization of this novel vector in the context of therapeutic gene delivery.
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PMID:Successful in vivo tumor targeting of prostate-specific membrane antigen with a highly efficient J591/PEI/DNA molecular conjugate. 1645 11

Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximately 300 mm3), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.
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PMID:Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. 1660 24

The prostate-specific membrane antigen (PSMA), a product of the folate hydrolase (FOLH1) gene, is highly expressed as a largely extracellular membrane-anchored protein in malignant prostate tissues and in nonprostatic tumor neovasculature. Treatment of prostate cancer LNCap cells with spliceswitching oligonucleotides (SSOs) modulated splicing of FOLH1 pre-mRNA from the full-length PSMA splice variant to three splice variants: the cytoplasmic PSM', alternatively spliced at exon 1, and the previously unexamined PSMADelta6 and PSMADelta18 variants, which lack exons 6 and 18, respectively. Application of SSOs decreased membrane PSMA levels and increased PSM', PSMADelta6, and PSMADelta18 transcripts. As a result, PSM' protein was translocated to the cytoplasm, and switching to PSMADelta6 and PSMADelta18 downregulated PSMA expression. NAALADase assays showed that PSM' retained enzymatic activity. PSMADelta6 and PSMADelta18 were not active, presumably due to a change in a reading frame that eliminated the NAALDase active site or the dimerization domain or both in these proteins.
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PMID:Analysis of prostate-specific membrane antigen splice variants in LNCap cells. 1676 42

A two-step transcriptional amplification system (TSTA) was used to enhance the efficacy of suicide gene therapy for treatment of prostate cancer. We designed a TSTA system and constructed two types of plasmid: one containing GAL4-VP16 fusion protein under the control of a tumor-specific promoter, the other containing luciferase or herpes simplex virus thymidine kinase (HSV-tk) under the control of a synthetic promoter. The TSTA systems using nanoparticles based on lipids were evaluated by measuring the amount of induced luciferase activity as a function of prostate-specific membrane antigen (PSMA) and midkine (Mk) promoters, specific for LNCaP and PC-3 prostate cancer cells, respectively. In LNCaP cells that were PSMA-positive, the TSTA system featuring the PSMA enhancer and promoter exhibited activity that was 640-fold greater than a system consisting of one-step transcription with the PSMA promoter. In contrast, this difference in activity did not occur in PSMA-negative PC-3 cells. In Mk-positive PC-3 cells, the TSTA system with the Mk promoter exhibited a five-fold increase in activity over one-step transcription, but such activity was not induced in Mk-negative LNCaP cells. When using HSV-tk for suicide gene therapy, TSTA systems featuring the PSMA or Mk promoter inhibited in vitro cell growth in the presence of ganciclovir. Furthermore, the TSTA system featuring the Mk promoter suppressed in vivo growth of PC-3 tumor xenografts to a greater extent than one-step transcription. These findings show that TSTA systems can enhance PSMA and Mk promoter activities and selectively inhibit PC-3 cell growth in tumors. This suggests that TSTA systems featuring tumor-specific promoters are suitable for cancer treatment by gene therapy.
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PMID:Two-step transcriptional amplification-lipid-based nanoparticles using PSMA or midkine promoter for suicide gene therapy in prostate cancer. 1680 Aug 21

Technologies that mediate targeted delivery of small interfering RNAs (siRNAs) are needed to improve their therapeutic efficacy and safety. Therefore, we have developed aptamer-siRNA chimeric RNAs capable of cell type-specific binding and delivery of functional siRNAs into cells. The aptamer portion of the chimeras mediates binding to PSMA, a cell-surface receptor overexpressed in prostate cancer cells and tumor vascular endothelium, whereas the siRNA portion targets the expression of survival genes. When applied to cells expressing PSMA, these RNAs are internalized and processed by Dicer, resulting in depletion of the siRNA target proteins and cell death. In contrast, the chimeras do not bind to or function in cells that do not express PSMA. These reagents also specifically inhibit tumor growth and mediate tumor regression in a xenograft model of prostate cancer. These studies demonstrate an approach for targeted delivery of siRNAs with numerous potential applications, including cancer therapeutics.
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PMID:Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. 2704 50

The recombinant prostate-specific PPT sequence comprises a prostate-specific antigen enhancer, a PSMA enhancer and a TARP promoter. It is transcriptionally active in human prostate cancer cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer, it has no detectable transcriptional activity. Herein, we describe that the PPT sequence in combination with a two-step transcriptional amplification (TSTA) system becomes active also in murine prostate cancer cells. An adenovirus with TSTA-amplified PPT-controlled expression of the luciferase reporter gene, Ad[PPT/TSTA-Luc], has up to 100-fold higher prostate-specific transcriptional activity than a non-amplified PPT-based adenovirus, Ad[PPT-Luc], in human cells. In addition, Ad[PPT/TSTA-Luc] confers prostate-specific transgene expression in murine cells, with an activity that is approximately 23% of Ad[CMV-Luc] in the transgenic adenocarcinoma of the mouse prostate (TRAMP)-C2 cells. Moreover, to visualize luciferase expression in living mice a charge-coupled device camera was used. Ad[PPT/TSTA-Luc] yielded approximately 30-fold higher transgene expression than Ad[PPT-Luc] in LNCaP tumor xenografts. Importantly, Ad[PPT/TSTA-Luc] also showed activity in murine TRAMP-C2 tumors, whereas Ad[PPT-Luc] activity was undetectable. These results highlight that the recombinant PPT sequence is active in murine prostate cancer cells when augmented by a TSTA system. This finding opens up for preclinical studies with prostate-specific therapeutic gene expression in immunocompetent mice.
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PMID:Two-step amplification of the human PPT sequence provides specific gene expression in an immunocompetent murine prostate cancer model. 1705 14

We previously reported that several DNA fragments from human prostate-specific membrane antigen (hPSM), mouse prostatic acid phosphatase (mPAP), and human prostate-specific antigen (hPSA) genes were selected and fused to create a novel hPSM-mPAP-hPSA fusion gene (named 3P gene), and human secondary lymphoid tissue chemokine (SLC), 3P, and human IgG Fc genes were inserted into pcDNA3.1 to construct a DNA vaccine, designated pSLC-3P-Fc. In this report, to establish a more efficient treatment for immunotherapy against prostate cancer, the construct was transfected into B16F10 to generate gene-modified tumor cell vaccine (named B16F10-SLC-3P-Fc). In poorly immunogenic B16F10 mouse melanoma model, the immunization with B16F10-SLC-3P-Fc resulted in a strong antitumor response and 50% of tumor-bearing mice achieved long-term survival (>120 days). In vivo depletion of lymphocytes indicated that CD8(+) T cells were involved in the direct tumor killing, whereas CD4(+) T lymphocytes were required for the induction of CD8(+) CTL response in B16F10-SLC-3P-Fc-immunized mice. Splenocytes from B16F10-SLC-3P-Fc-immunized mice specifically recognized and lysed PSM, PAP, PSA, and 3P expressing tumor cells. The combined therapy of B16F10-SLC-3P-Fc plus anti-B7-H1 MAbs further enhanced the immune response. Rechallenge experiment showed that a persistent memory response was successfully induced by the combined therapy. These observations suggest pSLC-3P-Fc-modified tumor cells could serve as a vaccine against prostate cancer, and the therapy combined with anti-B7-H1 MAbs further enhanced the antitumor immune response.
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PMID:Potent systemic antitumor immunity induced by vaccination with chemotactic-prostate tumor associated antigen gene-modified tumor cell and blockade of B7-H1. 1718 Apr 70

Multifunctional nanoparticle probes based on semiconductor quantum dots (QDs) are developed for simultaneous targeting and imaging of cancer cells in living animals. The structural design involves encapsulating luminescent QDs with an ABC triblock copolymer, and linking this polymer to tumor-targeting ligands, such as antibodies and drug-delivery functionalities. In vivo targeting studies of human prostate cancer growing in nude mouse show that the QD probes can be delivered to tumor sites by both enhanced permeation and retention (passive targeting) and by antibody binding to cancer-specific cell surface biomarkers such as prostate-specific membrane antigen (active targeting). Using both subcutaneous injection of QD-tagged cancer cells and the systemic injection of multifunctional QD probes, multicolor fluorescence imaging of as few as 10-100 cancer cells can be achieved under in vivo conditions. The use of spectrally resolved imaging can efficiently remove autofluorescence background and precisely delineate weak spectral signatures in vivo. These results suggest that QD probes and spectral imaging can be combined for multiplexed imaging and detection of genes, proteins, and small-molecule drugs in single living cells, and that this imaging modality can be adopted for real-time visualization of cancer cell metastasis in live animals.
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PMID:Quantum dots for in vivo molecular and cellular imaging. 1723 36


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