Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme.

BACKGROUND: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. METHODS: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks. RESULTS: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study. CONCLUSION: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.

Neurotoxicity of CI-980, a novel mitotic inhibitor.

CI-980 is a chemotherapeutic agent currently in Phase II trials that arrests cellular division by binding to tubulin. It is structurally and functionally similar to colchicine, a potent nonreversible neurotoxin, and is able to cross the blood-brain barrier. In Phase I studies, neurotoxicity was noted. The neurotoxicity of CI-980 was prospectively evaluated in two Phase II studies by neurological evaluation, quantitative sensory testing, and neuropsychological assessment of cognitive functioning. The results revealed a significant but reversible decline in recent memory functioning after each course of CI-980, with no effect on overall mental status or neurological function. Sixty-seven percent of patients performed in the impaired range on the memory test after their first infusion, whereas only one exhibited a decline on a brief cognitive screen. The results are consistent with the known effects of colchicine on the brain. Colchicine selectively blocks choline acetyltransferase in the hippocampus and basal forebrain, the area of the brain responsible for memory consolidation. Although the effect of CI-980 was reversible at the dose and schedule used, this study suggests that careful monitoring of cognitive function in patients receiving this agent should be performed if dose or schedule parameters are changed. In addition, this study demonstrates the feasibility of incorporating neuropsychological assessment in clinical trials of new anticancer agents having potential neurotoxic side effects.

The Pluto system: Initial results from its exploration by New Horizons.

The Pluto system was recently explored by NASA's New Horizons spacecraft, making closest approach on 14 July 2015. Pluto's surface displays diverse landforms, terrain ages, albedos, colors, and composition gradients. Evidence is found for a water-ice crust, geologically young surface units, surface ice convection, wind streaks, volatile transport, and glacial flow. Pluto's atmosphere is highly extended, with trace hydrocarbons, a global haze layer, and a surface pressure near 10 microbars. Pluto's diverse surface geology and long-term activity raise fundamental questions about how small planets remain active many billions of years after formation. Pluto's large moon Charon displays tectonics and evidence for a heterogeneous crustal composition; its north pole displays puzzling dark terrain. Small satellites Hydra and Nix have higher albedos than expected.

Subacute encephalopathic toxicity of cisplatin.

Acute blindness or seizures are usually the first signs of central neurotoxicity from cisplatin. We report a case of subacute neurotoxicity caused by cisplatin. Progressive encephalopathy and partial loss of vision were the main observed signs. This condition was completely reversible upon cisplatin discontinuation, as is usually the case with acute central neurotoxicity.

Immunochemical and immunohistochemical studies of cadmium associated proteins in Rana tadpoles.

Previous observations suggested that Rana tadpoles treated with aqueous cadmium (Cd) accumulate Cd in their liver and mesonephros. In order to study the response to Cd in these tissues we (a) exposed tadpoles in mid-limb bud stages to sublethal quantities of Cd, (b) isolated Cd-associated protein (CAP) from a liver cytosol fraction, (c) prepared a heterologous rabbit antiserum against glutaraldehyde-treated CAP (G-CAP), (d) used the rabbit anti-G-CAP antiserum in order to assess the tissue distribution of CAP in Cd-treated and untreated tadpoles, and (e) assessed species cross-reactivities of our anti-G-CAP with CAPs and metallothioneins (MTs) isolated from Cd-treated vertebrate liver cytosol fractions. We found that (a) CAP was present in higher quantities in liver cytosol obtained from Cd-treated tadpoles compared to liver cytosol obtained from untreated control tadpoles, (b) indirect immunofluorescent analysis revealed that CAP was localized in liver hepatocytes and kidney tubule epithelial cells in Cd-treated tadpoles, and (c) the anti-G-CAP crossreacted with rodent and fish CAP. These observations suggest that the developing liver and mesonephros are involved in responses to toxic metals and that our anti G-CAP antiserum may be used to gauge exposure to environmental Cd.

Advances in chemotherapy for brain tumors.

Malignant brain tumors, particularly those of glial origin, carry a dismal prognosis despite decades of therapeutic maneuvers. Surgery and radiotherapy have not been curative, and adjunctive chemotherapy has resulted only in modest increases in survival. This article discusses the current status of chemotherapy, the problems encountered with the interpretation of chemotherapeutic trials, and some of the new approaches currently being evaluated.

Examination of factor structure for the consumers' responses to the Value Consciousness Scale.

The psychometric properties of the Value Consciousness Scale developed by Lichtenstein, Netemeyer, and Burton in 1990 were examined in a retail grocery study (N = 497). Original assessment of scale properties was undertaken using two convenience samples in a nonretail setting and additional scale performance has been documented by the scale authors. This study furthers previous research by (1) examining performance on the items in the retail grocery setting and (2) utilizing an appropriately rigorous sampling procedure. A confirmatory factor analysis indicated that the Value Consciousness Scale does not exhibit unidimensional properties, and one must be cautious if this scale is used in applications of market segmentation until further clarification can be provided.

Oncolytic adenovirus retargeted to Delta-EGFR induces selective antiglioma activity.

The fact that glioblastomas, which are one of the most devastating cancers, frequently express the Delta-EGFR (epithelial growth factor receptor) also called mutant variant III of EGFR (EGFRvIII) suggests that this cancer cell-specific receptor might serve as an ideal target for cancer therapy. To assess its potential as such a target, we constructed an oncolytic adenovirus with Retargeted Infectivity Via EGFR (Delta-24-RIVER) on the backbone of Delta-24. This new oncolytic adenovirus targets, as Delta-24 does, the disrupted Rb pathway in cancer cells; in addition, this adenovirus has also been retargeted through the abrogation of CAR binding (Y477A mutation in adenoviral fiber protein) and insertion of an EGFRvIII-specific binding peptide in the HI loop of the fiber protein. As compared with Delta-24, Delta-24-RIVER induced EGFRvIII-selective cytotoxicity in U-87 MG isogenic cell lines and in tetracycline-inducible EGFRVIII expressing U-251 MG cells. Accordingly, by tittering the viral progeny and examining fiber protein expression in the above cells, we showed that the replication of this new construct also correlated with EGFRvIII expression. Consistently, immunohistochemistry staining of the adenoviral capsid protein hexon in the virus-treated tumors revealed that the virus replicated more efficiently in EGFRvIII-expressing U-87 MG.DeltaEGFR xenografts than in the tumors grown from U-87 MG cells. Importantly, treatment with Delta-24-RIVER prolonged the survival of animals with intracranial xenografts derived from U-87 MG.DeltaEGFR cells. Therefore, our results constitute the first proof of the direct targeting of a cancer-specific receptor using an oncolytic adenovirus.

Chemotherapy for metastatic tumors to the central nervous system.

Management of patients with central nervous system metastases poses numerous challenges. This review focuses on the use of chemotherapy in these patients, addressing treatment difficulties such as drug resistance and possible solutions. The impact of the blood-brain barrier is considered less of a limitation than once thought. The advent of targeted signal transduction inhibitors is noted in this context. The current efficacy of chemotherapeutic agents and combinations is also discussed, with results from large studies highlighting a positive survival trend for chemotherapy in selected tumor histologies.

Escherichia coli glycerol kinase. Cloning and sequencing of the glpK gene and the primary structure of the enzyme.

The glpK gene, which codes for Escherichia coli K-12 glycerol kinase (EC 2.1.7.30, ATP:glycerol 3-phosphotransferase), has been cloned into the HindIII site of pBR322. The gene was contained in a 2.8-kilobase DNA fragment which was obtained from a lambda transducing bacteriophage, lambda dglpK100 (Conrad, C.A., Stearns, G.W., III, Prater, W.E., Rheiner, J.A., and Johnson, J.R. (1984) Mol. Gen. Genet. 195, 376-378). The DNA sequence of 2 kilobases of the cloned HindIII fragment was obtained using the dideoxynucleotide method. The start of the open reading frame for the glpK gene was identified from the N-terminal sequence of the first 22 amino acid residues of the purified enzyme, which was determined by automated Edman degradation. The open reading frame codes for a protein of 502 amino acids and a molecular weight of 56,106 which is in good agreement with the value previously determined by sedimentation equilibrium. The primary structure of the protein as deduced from the gene sequence was corroborated by the isolation and sequencing of four tryptic peptides, which were found to occur at the following amino acid locations: 173-177, 203-211, 279-281, 464-468. The N-terminal sequence of the purified enzyme shows that the enzyme undergoes post-translational processing. Restriction digestion as well as DNA sequencing of the supercoiled plasmid shows that the HindIII fragment is inserted into pBR322 such that the glpK gene is transcribed in a counterclockwise direction. Examination of the upstream DNA sequence reveals two possible promoters of essentially the same efficiency: the P1 promoter of pBR322 and a hybrid promoter which contains both bacterial and pBR322 DNA sequences.

Characterization of a novel keratinocyte ubiquitin carrier protein.

A novel member of the ubiquitin carrier protein family, designated E2EPF, has been cloned by our laboratory and expressed in a bacterial system in an active form. Ubiquitin carrier proteins, or E2s, catalyze one step in a multistep process that leads to the covalent conjugation of ubiquitin to substrate proteins. In this paper, we show that recombinant E2EPF catalyzes auto/multiubiquitination, the conjugation of multiple ubiquitin molecules to itself. Multiubiquitination has been shown previously to be required for targeting of a substrate protein for rapid degradation. Using a rabbit reticulocyte lysate system, E2EPF was shown to support the degradation of a model substrate in an ATP- and ubiquitin-dependent fashion. In contrast to a previous study which showed that selective protein degradation in one system is dependent upon multiubiquitination via the lysine 48 residue of ubiquitin, multiubiquitination, and proteolytic targeting by E2EPF was shown here to be independent of the lysine 48 multiubiquitin linkage. This functional characterization of E2EPF revealed a combination of features that distinguishes this enzyme from all previously characterized members of the ubiquitin carrier protein family. These results also suggest several possible autoregulatory models for E2EPF involving auto- and multiubiquitination.

Characterization of a glpK transducing phage.

A specialized glpK transducing phage, lambda glpK100, has been isolated and characterized with respect to DNA structure. The glpK component of the glpKF operon has been localized within a 2.0 kilobase pair (kbp) region of the approximately 8.24 kbp bacterial DNA insert, and the positions of BamHI, EcoRI and HindIII restriction sites within this DNA have been identified.

Phase II study of i.v. CI-980 in patients with advanced platinum refractory epithelial ovarian carcinoma.

CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine site, inhibiting the polymerization of microtubules and arresting cellular division in metaphase. Myelosuppression and neurotoxicity were dose-limiting in phase I studies. Sixteen patients with stage III and IV platinum-refractory ovarian cancer received 4.5 mg/m2/day of CI-980 as a continuous i.v. infusion for 72 h, repeated every 3 weeks. Eleven patients had progression and four patients had stable disease. One patient (6%; 95% CI 0-25%) achieved a partial response after 9 months of treatment which lasted for 27 months. The overall median survival was 7 months. Grade 4 granulocytopenia occurred in five patients, with two episodes of neutropenic fever. Neurological toxicity was mild with 12 episodes of transient subclinical recent memory loss documented in four patients by specialized neuropsychological evaluations. One patient each had hallucinations and mild truncal ataxia, and four patients had mild, reversible neurosensory toxicity. One episode of severe hypoxemia and dyspnea occurred in a patient with chronic obstructive pulmonary disease. CI-980 has minimal activity and is tolerable in a population of heavily pretreated patients with platinum refractory ovarian cancer.