Pilot Preclinical and Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for PET/CT Imaging of Intracranial Malignancies.

Purpose: (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a novel radiopharmaceutical for Positron Emission Tomography (PET) imaging. It is a glutamate analogue that can be used to measure xC- transporter activity. This study was performed to assess the feasibility of 18F-FSPG for imaging orthotopic brain tumors in small animals and the translation of this approach in human subjects with intracranial malignancies.

18F-FAZA PET imaging response tracks the reoxygenation of tumors in mice upon treatment with the mitochondrial complex I inhibitor BAY 87-2243.

Purpose: We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity.

Experimental Design: Four PET tracers [(18)F-FDG, (18)F-Fpp(RGD)2, (18)F-FLT, and (18)F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle.

Specific PET imaging of xC- transporter activity using a ¹⁸F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism.

Purpose: (18)F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable ¹⁸F-labeled glutamate analogue for PET imaging of tumors.

Genome-wide gene expression profiling of formalin-fixed paraffin-embedded breast cancer core biopsies using microarrays.

The routine workflow for invasive cancer diagnostics includes biopsy processing by formalin fixation and paraffin embedding. It has been shown only recently that this kind of sample can be used for gene expression analysis with microarrays. To support this view, the authors conducted a microarray study using formalin-fixed paraffin-embedded (FFPE) core needle biopsies from breast cancers.

Reproducibility study of [(18)F]FPP(RGD)2 uptake in murine models of human tumor xenografts.

Purpose: An (18)F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer {[(18)F]FPP(RGD)(2)} has been used to image tumor α(v)β(3) integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin α(v)β(3)-targeted PET probe, [(18)F]FPP(RGD)(2,) using small animal PET.

Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer.

Background: Enhanced activity of histone deacetylases (HDAC) is associated with more aggressive tumour behaviour and tumour progression in various solid tumours. The over-expression of these proteins and their known functions in malignant neoplasms has led to the development of HDAC inhibitors (HDI) as new anti-neoplastic drugs. However, little is known about HDAC expression in renal cell cancer.

Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo.

Purpose: Recently, several studies reported a strong functional link between histone deacetylases (HDAC) and the development of tumors of the large intestine. However, despite the importance of these molecules, comparably little is known on expression patterns and functions of specific HDAC isoforms in colorectal cancer.

Experimental Design: We characterized class I HDAC isoform expression patterns in a cohort of 140 colorectal carcinomas by immunohistochemistry.

Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy.

High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer.

Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis.

Background: Although histone deacetylases (HDACs) are known to have an important regulatory role in cancer cells, and HDAC inhibitors (HDIs) have entered late-phase clinical trials for the treatment of several cancers, little is known about the expression patterns of HDAC isoforms in tumours. We aimed to clarify these expression patterns and identify potential diagnostic and prognostic uses of selected class I HDAC isoforms in gastric cancer.

Methods: Tissue samples from a training cohort and a validation cohort of patients with gastric cancer from two German institutions were used for analyses.

High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis.

Activation of nuclear factor-kappaB (NF-kappaB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kappaB subunit, in these carcinomas and possible correlations thereof with NF-kappaB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry.

Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappaB by tumor necrosis factor-alpha receptor-1 down-regulation.

Recently, the inhibition of histone deacetylase (HDAC) enzymes has attracted attention in the oncologic community as a new therapeutic opportunity for hematologic and solid tumors including non-small cell lung cancer (NSCLC). In hematologic malignancies, such as diffuse large B-cell lymphoma, the HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA), has recently entered phase II and III clinical trials. To further advance our understanding of their action on tumor cells, we investigated the possible effect of HDI treatment on the functionality of the nuclear factor-kappaB (NF-kappaB) pathway in NSCLC.

Molecular alterations after Polo-like kinase 1 mRNA suppression versus pharmacologic inhibition in cancer cells.

Multiple roles within mitosis have been assigned to Polo-like kinase 1 (Plk1), making it an attractive candidate for mitotic targeting of cancer cells. We have employed chimeric antisense oligonucleotides to investigate the molecular alterations after targeted interference with Plk1 in RKO human colon adenocarcinoma and PC3 prostate cancer cells. Suppression of Plk1 mRNA resulted in a dramatic increase of the mitotic index followed by the onset of apoptosis.

Expression patterns of polo-like kinase 1 in human gastric cancer.

Polo-like kinase 1 (PLK1) is centrally involved in the regulation of mitosis in normal and malignant cells. It is known that inhibition of PLK1 expression in vitro and in vivo leads to mitotic arrest, induction of apoptosis and suppression of tumor growth. In the present study, expression of PLK1 was investigated in paraffin tissue of 135 cases of gastric adenocarcinoma and in 46 corresponding lymph node metastases by immunohistochemistry.

G3139 and other CpG-containing immunostimulatory phosphorothioate oligodeoxynucleotides are potent suppressors of the growth of human tumor xenografts in nude mice.

Several phosphorothioate antisense oligodeoxynucleotides (ODN) are developed to target factors potentially involved in tumor growth and apoptosis suppression. Among them, the 18-mer G3139 (Oblimersen), which targets Bcl-2, is currently being tested in phase II and phase III clinical trials for various tumors in combination with chemotherapy. On the other hand, ODNs containing CpG dinucleotides (CpG-ODN) within specific-sequence contexts (CpG motifs) have been shown to activate rodent or primate immune cells via toll-like receptor 9 (TLR9) and have demonstrated remarkable T cell-dependent antitumor efficacy in a series of murine tumor models.

Polo-like kinase 1 expression is a prognostic factor in human colon cancer.

Aim: To clarify the expression patterns and prognostic implications of the mitotic regulator Polo-like kinase 1 (PLK1) in colon cancer.

Methods: Expression of PLK1 was investigated by immunohistochemistry (158 cases) and immunoblotting in tissue of colon adenomas and adenocarcinomas. PLK1 expression patterns were correlated with clinicopathological parameters and patient prognosis.

Overexpression of Polo-like kinase 1 is a common and early event in pancreatic cancer.

Background: There is abundant evidence from in vivo and in vitro studies that Polo-like kinase 1 (PLK1) plays a crucial role in the regulation of proliferative activity of normal and malignant cells. Therefore, PLK1 has been proposed as a new target for antineoplastic treatment strategies.

Methods: We conducted an immunohistochemical expression study for PLK1 on 86 cases of pancreatic adenocarcinoma as well as on 5 cases of chronic pancreatitis.

Polo-like kinase isoforms in breast cancer: expression patterns and prognostic implications.

Polo-like kinase (PLK) family members are known to be functionally involved in mitotic signaling and in cytoskeletal reorganization in both normal and malignant cells. In this study, expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimens of 135 breast carcinomas, and expression was correlated with clinicopathological parameters and patient prognosis. Strong PLK isoform overexpression was observed in 42.

Apoptotic responsiveness of PC-3 prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand: evidence for differential effects of Bcl-xL and Bcl-2 down-regulation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is cytotoxic to the majority of cancer cells while sparing most normal cells. However, different prostate carcinoma cell lines respond with different sensitivities to TRAIL, urging us to disclose the mechanisms that determine TRAIL sensitivity in prostate cancer cells, i.e.

Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta.

Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades.

Background: Polo-like kinase 1 (PLK1) is known to be one of the key players in the regulation of mitosis of both normal and malignant transformed cells. Moreover, several studies reported an overexpression of PLK1 in human malignancies compared to the corresponding tissue of origin.

Methods: In this study, expression of PLK1 was investigated by immunohistochemistry in 78 tissue specimens of prostate carcinoma and in adjacent normal prostate tissue as well as in benign prostate hyperplasia.

Changes in gene expression induced by phosphorothioate oligodeoxynucleotides (including G3139) in PC3 prostate carcinoma cells are recapitulated at least in part by treatment with interferon-beta and -gamma.

Purpose: G3139 is an antisense bcl-2 phosphorothioate oligodeoxyribonucleotide that is currently being evaluated in Phase III clinical trials in several human cancers. The aim of the present work was to further identify the apparent non-bcl-2-dependent mechanism of this action of this compound in PC3 prostate cancer cells.

Experimental Design: We performed Affymetrix U95A oligonucleotide microarray studies on mRNA isolated from cells treated with G3139 and related oligonucleotides.

Down-regulation of protein kinase Ceta by antisense oligonucleotides sensitises A549 lung cancer cells to vincristine and paclitaxel.

Previous studies point to protein kinase C (PKC) isozyme eta as a resistance factor in cancer cells. Therefore, we investigated whether down-regulation of PKCeta with second generation antisense oligonucleotides (ODNs) would sensitise A549 human lung carcinoma cells to cytostatics. The effects were compared to the outcome of Bcl-xL down-regulation.

Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma.

The Polo-like kinase (PLK) family comprises three serine/threonine kinases, functionally involved in signal transduction pathways essential for the accomplishment of mitosis in both normal and malignant cells. Moreover, certain PLKs have been functionally linked to cytoskeletal reorganisation. In this study, the expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimen of normal ovaries (n=9), cystadenomas (n=17), borderline tumours (n=13) and ovarian carcinomas (n=77).

Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis.

In this study expression of protein kinase C alpha (PKCalpha), delta (PKCdelta) and iota (PKCiota) was determined immunohistochemically in formalin-fixed paraffin-embedded tissue specimen of ovarian cystadenomas (n=7), borderline tumours of the ovary (n=8), primary (n=54) and recurrent invasive ovarian carcinomas (n=13). The expression was correlated with clinicopathological parameters and patient survival. In addition, expression of PKCiota was assessed in 3 ovarian carcinoma cell lines (OVCAR-3, SKOV-3, OAW-42) and in one human ovarian surface epithelium (HOSE) cell line.

Induction of drug resistance and protein kinase C genes in A2780 ovarian cancer cells after incubation with antineoplastic agents at sublethal concentrations.

We examined the inducibility of drug resistance (MDR1, MRP1, LRP) and protein kinase C (PKC) isozyme (alpha, epsilon, eta, theta, tau, zeta) corresponding genes in A2780 ovarian cancer cells after a 24-hour treatment with adriamycin (ADR), camptothecin (CAM), etoposide (ETO) or vincristine (VCR). Sublethal concentrations of drugs were used to exclude short-term effects caused by selection. Cell cycle analysis was performed to identify possible correlation between resistance factors, PKC isozymes and proliferation.