Inhibition of phospholipase C-gamma1 activation blocks glioma cell motility and invasion of fetal rat brain aggregates.

Objective: Phospholipase C (PLC)-gamma is a cytosolic enzyme activated by several growth factor (GF) receptors (epidermal GF receptor [EGFR], platelet-derived GF receptor, and insulin-like GF 1 receptor), and its activation is associated with increased cell motility (but not cell proliferation) in nonglioma cell lines. Because up-regulated activation of EGFR has been consistently linked to poor patient survival in patients with glioblastoma multiforme (GBM) and because inhibition of EGFR activation by tyrosine kinase inhibitors prevents glioma infiltration in vitro, we hypothesized that inhibition of PLC-gamma activation would inhibit glioma cell invasiveness.

Methods: Our experimental model assesses tumor spheroid invasion of fetal rat brain spheroids by confocal microscopy.

The DiGeorge anomaly (CATCH 22, DiGeorge/velocardiofacial syndrome).

The DiGeorge anomaly (DGA), originally considered a clinical paradigm for isolated thymus deficiency, has now been redefined as a member of a group of disorders that share in common a chromosome deletion, which results in monosomy 22q11 (CATCH-22 or DiGeorge/velocardiofacial [VCFS] syndrome). In addition to the thymus defect, conotruncal heart anomalies, dysmorphism, hypoparathyroidism, and cleft palate are prominent features. Despite the emphasis on thymus involvement in DGA, a clinically significant thymus defect is found only in a small percentage of these patients.

Adriamycin: protection from cell death by removal of extracellular drug.

Adriamycin is a cytotoxic drug which has enjoyed considerable success in the treatment of cancer. This agent has a bewildering variety of biological effects both within and on the surface of cells exposed to drug, and it has proved difficult to unambiguously assign a single mechanism of action. In this report we are able to separate intracellular and extracellular actions by taking advantage of the complete lack of Adriamycin-induced cytotoxicity at low temperature.

Enhanced Ia expression by alveolar macrophages following intratracheal administration of bleomycin to rats.

Bleomycin is an important anticancer drug that causes severe, and sometimes life-threatening, pulmonary toxicity. Initially, there is an acute inflammation followed by an irreversible pulmonary fibrosis. Our studies have focussed on the effects of the acute pulmonary inflammation on the state of alveolar macrophage activation.

Paraneoplastic encephalomyelitis. Dramatic response to chemotherapy alone.

Neurologic paraneoplastic syndromes are usually a debilitating and untreatable manifestation of malignancy. The case is presented of a woman with severe paraneoplastic encephalomyelitis that was characterized predominantly by cerebellar degeneration associated with small cell lung cancer, both of which responded rapidly to cytotoxic chemotherapy alone. She is alive with some neurologic residua but no signs of recurrent cancer more than 2 years after diagnosis.

Formation of nitric oxide hemoglobin in erythrocytes co-cultured with alveolar macrophages taken from bleomycin treated rats.

Alveolar macrophages, taken from rats treated with a single intratracheal dose of bleomycin, release reactive nitrogen intermediates in the form of nitric oxide which are cytostatic to murine leukemia L1210 cells. When cultured in the presence of erythrocytes the cytostatic activity of alveolar macrophages was inhibited which corresponded with an increase in nitrosylated hemoglobin content when compared with erythrocytes cultured alone. These results suggest that erythrocytes inhibit alveolar macrophage cytostatic activity by preventing reactive nitrogen intermediates from reaching target cells because the hemoglobin serves as a sink for reactive nitrogen intermediates in the form of nitric oxide.

A phase I clinical trial of didemnin B.

Didemnin B is a depsipeptide extracted from the marine tunicate Trididemnin cyanophorum. This agent is a potent inhibitor of L1210 growth in vitro and has activity against murine B16 melanoma, P388 leukemia, and M5076 sarcoma in vivo. The results of preclinical toxicologic tests demonstrated abnormalities in clotting parameters thought to be secondary to drug-induced liver dysfunction.

DNA repair and mutant frequency in schizophrenia.

The in vivo frequency of mutants resulting from mutation at the hprt locus in human T-lymphocytes was determined with a cloning assay. T-lymphocytes were obtained from 14 individuals diagnosed with schizophrenia and 5 controls. No significant difference in mutant frequency was observed between the 2 groups.

In vivo ionizing irradiations produce deletions in the hprt gene of human T-lymphocytes.

The hprt T-lymphocyte cloning assay, which detects mutations occurring in vivo in humans, has been used to examine mutants induced in patients receiving radioimmunoglobulin therapy (RIT) for cancer. Samples from 13 patients before treatment (controls) and 15 samples from 12 patients after treatment were studied for both mutant frequencies and molecular changes in the hprt mutant T-cell clones. Patients were studied up to 48 months after treatment.

Shikimic acid complexes of platinum. Preparation, reactivity, and antitumor activity of (R,R-1,2-diaminocyclohexane) bis(shikimato) platinum(II). Evidence for a novel rearrangement involving platinum-carbon bond formation.

The complex (R,R-1,2-diaminocyclohexane)bis(shikimato)platinum(II) (shikimato = the anion of 3R,4S,5R-trihydroxy-1-cyclohexene-1-carboxylic acid), I, has been synthesized and purified by high performance liquid chromatography (HPLC). The complex is only moderately stable in aqueous solution. Its major hydrolysis product, also purified by HPLC, is proposed to be a unique complex type in which a single shikimate group is coordinated through both the carboxylate oxygen and the C(2) vinylic carbon of the shikimate moiety [Pt(R,R-dach)(O,C-shikimato)], II.

Analysis of human HPRT deletion mutations with X-linked probes and pulsed field gel electrophoresis.

Because the human hprt gene is used in numerous mutation studies, it is important to fully characterize this gene. Therefore, our laboratory has undertaken to map the region around the hprt gene at band q26 of the human X chromosome. Utilizing hprt mutant T-cell clones isolated using the hprt clonal assay, which have deletions of all or part of the hprt gene, we have ordered 5 anonymous probes previously known to map in Xq26.

Phase I trial of intraperitoneal recombinant interleukin-2/lymphokine-activated killer cells in patients with ovarian cancer.

Ten patients with ovarian cancer refractory to conventional therapy were treated with intraperitoneal (i.p.) recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK).

Molecular analysis of in vivo hprt mutations in human T lymphocytes. V. Effects of total body irradiation secondary to radioimmunoglobulin therapy (RIT).

The hprt (hypoxanthine guanine phosphoribosyltransferase) T cell cloning assay was used to detect in vivo mutations in T lymphocytes of individuals receiving radioimmunoglobulin therapy (RIT). A total of 28 patients receiving 131I and/or 90Y-labeled antiferritin antibodies was studied. Mutant frequencies for patients were clearly much higher than for historic non-treated controls (median 68.

Acute pancreatitis complicating therapy of Hodgkin disease: a case report.

Acute pancreatitis developed in a young woman with disseminated Hodgkin disease coincident with cytotoxic treatment. Despite concerns about possible drug-related causes, chemotherapy was continued without further gastrointestinal consequences. This case indicates that pancreatitis need not necessarily alter therapeutic plans for Hodgkin disease.

Interaction of novel bis(platinum) complexes with DNA.

Bis(platinum) complexes [[cis-PtCl2(NH3)]2H2N(CH2)nNH2] are a novel series of potential anticancer agents in which two cis-diamine(platinum) groups are linked by an alkyldiamine of variable length. These complexes are potentially tetrafunctional, a unique feature in comparison with known anticancer agents. Studies of DNA interactions of bis(platinum) complexes in comparison with cisplatin demonstrate significant differences.

Effect of cytotoxic monoclonal antibody depletion of T-lymphocyte subpopulations on bleomycin-induced lung damage in C57BL/6J mice.

Treatment of cancer patients with the antitumor antibiotic bleomycin (BLM) is associated with lung damage which can progress to pulmonary fibrosis. Shortly after intratracheal (it) administration of BLM to experimental animals there is an influx of inflammatory cells into the lung. These inflammatory cells, consisting primarily of polymorphonuclear cells, monocytes and lymphocytes, are believed to modulate the pathogenesis of pulmonary fibrosis.

Alteration of bronchoalveolar lavage cell populations following bleomycin treatment in mice.

Clinical use of the antitumor antibiotic bleomycin (BLM) is associated with the development of interstitial pulmonary fibrosis. Shortly after acute lung damage caused by intratracheal (it) administration of BLM to experimental animals there is an influx of inflammatory cells which are believed to modulate the process of fibrosis. This study was undertaken to determine what subpopulations of lymphocytes were in the bronchoalveolar lavage (BAL) cell population of C57BL/6J mice at various times after a single it dose of BLM and to determine whether BAL T-lymphocytes were activated after BLM treatment.

Prolymphocytic transformation of chronic lymphocytic leukemia: a case report of lengthy survival after intensive chemotherapy.

A case of prolymphocytic transformation of chronic lymphocytic leukemia (CLL) is presented in which complete peripheral morphometric remission and lengthy survival were observed after intensive chemotherapy. The case is discussed within the context of the reported therapeutic experience.

Specific alterations in the biological activities of C-20'-modified vinblastine congeners.

Both the anti-tumor and toxic activities of the vinca alkaloid dimers, vinblastine (VBL) and vincristine (VCR), may reside at the level of their known cellular target, the microtubule system. The contributions made by each of the various actions of these alkaloids on this system are unknown. We have used new, complete synthetic methodologies to create a series of eight C-20' alkyl congeners of VBL and have examined these compounds for their abilities to (1) inhibit microtubule assembly, (2) disassemble preformed microtubules, and (3) induce spiral aggregate formation, using purified brain microtubule protein.

Breast cancer and aging.

While many of the basic principles of breast cancer management are the same for younger and older women, a number of breast cancer issues particularly important for elderly women have not been resolved. Many of these management questions need answers based on data that are better than that currently available. At what age should the clinician consider cessation of screening mammography? For which very elderly patients might tamoxifen alone be adequate treatment for primary operable breast cancer? How can we develop better guidelines for the selection and administration of cytotoxic chemotherapy in an elderly population? What is the appropriate systemic adjuvant therapy, if any, for the patient over the age of 70? These and other questions may be answered through the development of clinical trials directed specifically at the elderly population.

Synthesis and antitumor activity of a series of (aminoethylpyrrolidine) platinum complexes.

A series of aminoethylpyrrolidine-platinum complexes were synthesized and partially characterized for chemical structure. The leaving groups in this series of complexes were varied in an attempt to identify cytotoxic, water-soluble aminoethylpyrrolidine-platinum complexes. The cytotoxic activity was tested in vitro against L1210 cells sensitive to cis-diamminedichloroplatinum(II) (L1210/0), L1210 cells resistant to cis-diamminedichloroplatinum(II) (L1210/DDP), and L1210 cells resistant to 1,2-diaminocyclohexane platinum (L1210/DACH).

Longitudinal study of the in vivo hprt mutant frequency in human T-lymphocytes as determined by a cell cloning assay.

The in vivo frequency of mutants resulting from mutation at the hprt locus in human T-lymphocytes can be determined by a cloning assay. This assay quantifies the frequency of 6-thioguanine-resistant (TGr) T-cells through growth of colonies in 96-well microtiter dishes. The reproducibility of the TGr mutant frequency values has now been assessed in a longitudinal study of six individuals (three male, three female, aged 22-33 years) employing 4-5 blood samples over a 26-37 week time period.

Immobilized adriamycin: toxic potential in vivo and in vitro.

We report experiments which test the toxicity of a new potential therapeutic agent, agarose-bound adriamycin (ImA). In C57Bl/6N mice this preparation is almost completely devoid of untoward effects when administered intraperitoneally; ImA lacks all the usual toxic repercussions of free adriamycin including abdominal adhesions, inflammatory peritonitis, weight loss and cardiotoxicity. The immobilized adriamycin is also inactive in a fetal mouse heart model of cardiac toxicity.

Continuous infusion homoharringtonine (NSC 141633) in refractory acute nonlymphocytic leukemia. An ECOG pilot study.

Single-agent homoharringtonine (HH) was evaluated as induction therapy in 20 patients with advanced acute nonlymphocytic leukemia (ANLL) in a pilot study of the Eastern Cooperative Oncology Group (ECOG). HH was given by continuous intravenous (i.v.