An Analysis of Recent FDA Oncology Scientific Publications.

In addition to its primary regulatory role, the Office of Hematology and Oncology Products at the U.S. Food and Drug Administration (FDA) is engaged in many forms of scientific authorship.

Using database linkages to measure innovation, commercialization, and survival of small businesses.

Here, we report the results of an outcomes evaluation of the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Programs at the National Institute of General Medical Sciences (NIGMS). Since the programs' inception, assessments of the SBIR/STTR programs at several federal agencies have utilized surveys of former grantees as the primary source of data. Response rates have typically been low, making non-response bias a potential threat to the validity of some of these studies' results.

Geographically-related outcomes of U.S. funding for small business research and development: Results of the research grant programs of a component of the National Institutes of Health.

This article examines the geographic distribution of funding for the U.S. Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs sponsored by the National Institute of General Medical Sciences (NIGMS).

NIH funding longevity by gender.

Women have achieved parity with men among biomedical science degree holders but remain underrepresented in academic positions. The National Institutes of Health (NIH)-the world's largest public funder of biomedical research-receives less than one-third of its new grant applications from women. Correspondingly, women compose less than one-third of NIH research grantees, even though they are as successful as men in obtaining first-time grants.

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy.

Despite improvements in the management of liver cancer, the survival rate for patients with hepatocellular carcinoma (HCC) remains dismal. The survival benefit of systemic chemotherapy for the treatment of liver cancer is only marginal. Although the reasons for treatment failure are multifactorial, intrinsic resistance to chemotherapy plays a primary role.

Multidrug resistance-linked gene signature predicts overall survival of patients with primary ovarian serous carcinoma.

Purpose: This study assesses the ability of multidrug resistance (MDR)-associated gene expression patterns to predict survival in patients with newly diagnosed carcinoma of the ovary. The scope of this research differs substantially from that of previous reports, as a very large set of genes was evaluated whose expression has been shown to affect response to chemotherapy.

Experimental Design: We applied a customized TaqMan low density array, a highly sensitive and specific assay, to study the expression profiles of 380 MDR-linked genes in 80 tumor specimens collected at initial surgery to debulk primary serous carcinoma.

Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance.

Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has been uncertain. Using a state-of-the-art Taqman-based quantitative RT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in established cancer cell lines (grown in monolayer, 3D scaffold, or in xenograft) and clinical samples, either containing >75% tumor cells or microdissected. The MDR transcriptome was determined a priori based on an extensive curation of the literature published during the last three decades, which led to the enumeration of 380 genes.

Clinical relevance of multidrug resistance gene expression in ovarian serous carcinoma effusions.

The presence of tumor cells in effusions within serosal cavities is a clinical manifestation of advanced-stage cancer and is generally associated with poor survival. Identifying molecular targets may help to design efficient treatments to eradicate these aggressive cancer cells and improve patient survival. Using a state-of-the-art TaqMan-based qRT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of 32 unpaired ovarian serous carcinoma effusion samples obtained at diagnosis or at disease recurrence following chemotherapy.

Enhancement of drug absorption through the blood-brain barrier and inhibition of intercellular tight junction resealing by E-cadherin peptides.

E-cadherin-mediated cell-cell interactions in the zonula adherens play an important role in the formation of the intercellular tight junctions found in the blood-brain barrier. However, it is also responsible for the low permeation of drugs into the brain. In this study, HAV6 peptide derived from the EC1 domain of E-cadherin was found to enhance the permeation of ¹⁴C-mannitol and [³H(G)]-daunomycin through the blood-brain barrier of the in situ rat brain perfusion model.

Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics.

Background: Cancer stem cells are presumed to have virtually unlimited proliferative and self-renewal abilities and to be highly resistant to chemotherapy, a feature that is associated with overexpression of ATP-binding cassette transporters. We investigated whether prolonged continuous selection of cells for drug resistance enriches cultures for cancer stem-like cells.

Methods: Cancer stem cells were defined as CD44+/CD24⁻ cells that could self-renew (ie, generate cells with the tumorigenic CD44+/CD24⁻ phenotype), differentiate, invade, and form tumors in vivo.

Analysis of expression of drug resistance-linked ABC transporters in cancer cells by quantitative RT-PCR.

Quantitative real-time PCR (qRT-PCR) boasts many advantages over microarrays. For instance, very low amounts of total RNA are required to yield highly accurate and reproducible detection of transcript levels. As a consequence, qRT-PCR has become a popular technique for assessing gene expression levels and is now the gold standard.

Molecular mechanisms of drug resistance in single-step and multi-step drug-selected cancer cells.

Multidrug resistance (MDR) remains one of the key determinants in chemotherapeutic success of cancer patients. Often, acquired resistance is mediated by the overexpression of ATP-binding cassette (ABC) drug transporters. To study the mechanisms involved in the MDR phenotype, investigators have generated a variety of in vitro cell culture models using both multi-step and single-step drug selections.

Evaluation of current methods used to analyze the expression profiles of ATP-binding cassette transporters yields an improved drug-discovery database.

The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by multiple mechanisms. These mechanisms can act individually or synergistically, leading to MDR, in which the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered.

Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies.

Overexpression of ATP-binding cassette (ABC) drug transporters that actively efflux a variety of amphipathic compounds can cause multidrug resistance (MDR) in cancer cells, which is a major obstacle in the success of cancer chemotherapy. The development of synthetic small molecule compounds or the identification of natural products that block ABC transporter-mediated efflux has been the conventional approach used to combat MDR. The strategy of using chemosensitizers, however, has not been successful in clinical cancer chemotherapy.

Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics.

Introduction: Whether cancer stem cells occur in BRCA1-associated breast cancer and contribute to therapeutic response is not known.

Methods: We generated and characterized 16 cell lines from five distinct Brca1deficient mouse mammary tumors with respect to their cancer stem cell characteristics.

Results: All cell lines derived from one tumor included increased numbers of CD44+/CD24- cells, which were previously identified as human breast cancer stem cells.

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance linked ABCG2 transporter.

Multidrug resistance due to reduced drug accumulation is a phenomenon predominantly caused by the overexpression of members of the ATP-binding cassette (ABC) transporters, including ABCB1 (P-glycoprotein), ABCG2, and several ABCC family members [multidrug resistance-associated protein (MRP)]. We previously reported that a thiosemicarbazone derivative, NSC73306, is cytotoxic to carcinoma cells that overexpress functional P-glycoprotein, and it resensitizes these cells to chemotherapeutics. In this study, we investigated the effect of NSC73306 on cells overexpressing other ABC drug transporters, including ABCG2, MRP1, MRP4, and MRP5.

ABC drug transporters as molecular targets for the prevention of multidrug resistance and drug-drug interactions.

ABC transporters play an important role in mediating the cytoplasmic concentration of endogenous and xenobiotic substances. They therefore influence the pharmacokinetic profile of a variety of drugs. By virtue of their localization to plasma membranes in the intestine, liver, blood-brain and other vital biological barriers, a majority of ABC drug transporters cause drug-drug interactions, decreased drug efficacy and multidrug resistance for chemotherapeutic agents.

A "silent" polymorphism in the MDR1 gene changes substrate specificity.

Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp.

Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor.

Cell cycle kinase inhibitors have advanced into clinical trials in oncology. One such molecule, JNJ-7706621, is a broad-spectrum inhibitor of the cyclin-dependent kinases and Aurora kinases that mediate G(2)-M arrest and inhibits tumor growth in xenograft models. To determine the putative mechanisms of resistance to JNJ-7706621 that might be encountered in the clinic, the human epithelial cervical carcinoma cell line (HeLa) was exposed to incrementally increasing concentrations of JNJ-7706621.

Plasma membrane calcium ATPase (PMCA4): a housekeeper for RT-PCR relative quantification of polytopic membrane proteins.

Background: Although relative quantification of real-time RT-PCR data can provide valuable information, one limitation remains the selection of an appropriate reference gene. No one gene has emerged as a universal reference gene and much debate surrounds some of the more commonly used reference genes, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). At this time, no gene encoding for a plasma membrane protein serves as a reference gene, and relative quantification of plasma membrane proteins is performed with genes encoding soluble proteins, which differ greatly in quantity and in targeting and trafficking from plasma membrane proteins.

Comparison of drug transporter levels in normal colon, colon cancer, and Caco-2 cells: impact on drug disposition and discovery.

A critical step in early phase drug development is the determination of oral bioavailability. In part, the ability to predict whether a drug will be effectively transported across the gastrointestinal mucosa can be estimated from the physicochemical properties of the compound. Although advancements through rational drug design have more correctly predicted bioavailability, considerable variability remains to be explained.

Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5).

Plant flavonoids are polyphenolic compounds, commonly found in vegetables, fruits and many food sources that form a significant portion of our diet. These compounds have been shown to interact with several ATP-binding cassette transporters that are linked with anticancer and antiviral drug resistance and, as such, may be beneficial in modulating drug resistance. This study investigates the interactions of six common polyphenols; quercetin, silymarin, resveratrol, naringenin, daidzein and hesperetin with the multidrug-resistance-associated proteins, MRP1, MRP4 and MRP5.

Modulation of cell adhesion molecules in various epithelial cell lines after treatment with PP2.

Regulation and expression of E-cadherin and other adhesion molecules were evaluated after exposure to a selective inhibitor of the Src family of tyrosine kinases and inducer of E-cadherin, PP2. E-cadherin is located within the intercellular junction, and it is involved in the management of paracellular permeability of various epithelial barriers in the body. Epithelial cell lines HCT-116, HT29, Caco-2, LS174T, and ARPE-19 were examined for morphological, functional, protein, and mRNA changes following 20 microM PP2 treatment.

Effects of an E-cadherin-derived peptide on the gene expression of Caco-2 cells.

Purpose: The goal of this study was to determine the effects of exposure to an HAV peptide (Ac-SHAVSS-NH2) on the protein and gene expression in Caco-2 cells, a model for the intestinal mucosa.

Methods: Caco-2 cells were incubated with either 100 or 500 microM of the hexapeptide then evaluated over a 48-h time period.

Results: Cell detachment from the monolayer was seen only after 48 h of exposure to the peptide, with the greatest effects occurring with a peptide concentration of 500 microM.