Mechanisms of uptake and resistance to troxacitabine, a novel deoxycytidine nucleoside analogue, in human leukemic and solid tumor cell lines.

Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytidine), a deoxycytidine analogue with an unusual dioxolane structure and nonnatural L-configuration, has potent antitumor activity in animal models and is in clinical trials against human malignancies. The current work was undertaken to identify potential biochemical mechanisms of resistance to troxacitabine and to determine whether there are differences in resistance mechanisms between troxacitabine, gemcitabine, and cytarabine in human leukemic and solid tumor cell lines. The CCRF-CEM leukemia cell line was highly sensitive to the antiproliferative effects of troxacitabine, gemcitabine, and cytarabine with inhibition of proliferation by 50% observed at 160, 20, and 10 nM, respectively, whereas a deoxycytidine kinase (dCK)-deficient variant (CEM/dCK(-)) was resistant to all three drugs.

Biomonitoring of urinary tamoxifen and its metabolites from breast cancer patients using nonaqueous capillary electrophoresis with electrospray mass spectrometry.

Tamoxifen is an antiestrogen drug used to treat breast cancer. We have extracted tamoxifen and several of its metabolites from urine of patients with both metastatic (stage IV) and locally confined (stages I, II, and III) breast cancer. Analysis of these metabolites was performed by nonaqueous capillary electrophoresis with electrospray-mass spectrometry.

Expression of high Km 5'-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia.

Cytarabine (ara-C) requires activation into its triphosphorylated form, ara-CTP, to exert cytotoxic activity. Cytoplasmic 5'-nucleotidase (5NT) dephosphorylates ara-CMP, a key intermediate, preventing accumulation of ara-CTP and may reduce cellular sensitivity to the cytotoxic activity of ara-C. To determine whether the level of expression of 5NT is correlated with clinical outcome in patients with acute myeloid leukemia (AML) treated with ara-C, this study analyzed the levels of messenger RNA expression of high Km 5NT by real-time polymerase chain reaction at diagnosis in blast cells of 108 patients with AML.

Acute abdominal symptoms and signs in children and young adults with spina bifida: ten years' experience.

Background/purpose: Diagnosis and management of the acute abdomen in patients with spina bifida (SB) can be problematic. There are at least 4 clinical factors that can predispose to the development of acute abdominal symptoms and signs, and patients with a thoracic level lesion can have a partially insensate abdomen. The authors analyzed their accumulated experience to determine the annual incidence of acute abdominal signs and symptoms in children and young adults with spina bifida, the differential diagnosis, the operative management, and the outcome.

Enteropathogenic Escherichia coli and ulcerative colitis in cotton-top tamarins (Saguinus oedipus).

The cotton-top tamarin (CTT; Saguinus oedipus) is an endangered New World primate that develops a highly prevalent idiopathic colitis resembling human ulcerative colitis. This study found that enteropathogenic Escherichia coli (EPEC) caused acute colitis in CTTs, which was associated with ulcerative colitis. EPEC clinical isolates revealed localized adherence patterns by HEp-2 assay and were devoid of Shiga-toxin production.

Nucleoside analogues: mechanisms of drug resistance and reversal strategies.

Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution.

Frequency of celiac disease in individuals with Down syndrome in the United States.

Ninety-three individuals with Down syndrome (DS) were screened to investigate the prevalence of celiac disease (CD) in the United States. Five of the 93 individuals were antiendomysial antibody (EMA) positive. Of the 5 who tested positive for EMA, 4 were biopsied, 1 refused biopsy.

Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.

Purpose: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder.

Methods: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II.

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche).

Identification of enteropathogenic Escherichia coli in simian immunodeficiency virus-infected infant and adult rhesus macaques.

Enteropathogenic Escherichia coli (EPEC) was recognized as a common opportunistic pathogen of simian immunodeficiency virus-infected rhesus macaques (Macaca mulatta) with AIDS. Retrospective analysis revealed that 27 of 96 (28.1%) animals with AIDS had features of EPEC infection, and EPEC was the most frequent pathogen of the gastrointestinal tract identified morphologically.

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

Purpose: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer.

Patients And Methods: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles.

Results: After an independent panel review, the overall objective response rate was 77% (complete response, 6%).

AKAP-mediated targeting of protein kinase a regulates contractility in cardiac myocytes.

Compartmentalization of cAMP-dependent protein kinase A (PKA) by A-kinase anchoring proteins (AKAPs) targets PKA to distinct subcellular locations in many cell types. However, the question of whether AKAP-mediated PKA anchoring in the heart regulates cardiac contractile function has not been addressed. We disrupted AKAP-mediated PKA anchoring in cardiac myocytes by introducing, via adenovirus-mediated gene transfer, Ht31, a peptide that binds the PKA regulatory subunit type II (RII) with high affinity.

Concurrent weekly carboplatin and radiotherapy for nasopharyngeal carcinoma: report of a joint phase II study.

We report a phase I/II study of weekly concurrent carboplatin and radiotherapy in patients with nasopharyngeal carcinoma (M0 stage). Of 47 patients registered, 45 completed the treatment course. Twenty-six (55%) (95% CI, 41-69%) patients experienced > or =grade 3 acute toxicity (RTOG).

Effectiveness of remifentanil versus traditional fentanyl-based anesthetic in high-risk outpatient surgery.

Study Objective: To determine if remifentanil would offer a superior hemodynamic and recovery profile compared to the current standard of care, which implements a fentanyl-based technique.

Design: Randomized, single-blind study.

Setting: Outpatient center associated with tertiary care center.

The cancer patient with chronic pain due to herpes zoster.

Postherpetic neuralgia (PHN) is the most common complication of herpes zoster, and as such has been an area of extensive medical research for the past three decades. The patients at highest risk for PHN include those older than 50 years, those with severe acute cases of zoster, and those with shingles in a trigeminal distribution. As persons with malignancy are at a high risk for developing zoster itself, PHN is a complication that will be faced by many of these patients and their caregivers.

Docetaxel (Taxotere) in combination with anthracyclines in the treatment of breast cancer.

Considering the single-agent activity of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and doxorubicin in breast cancer and their potential non-cross-resistance, several docetaxel/anthracycline-based combination chemotherapies were developed in phase I and II programs for metastatic breast cancer patients. The rationale for these combinations was also reinforced by the fact that docetaxel showed significant activity in phase III trials in patients previously exposed or having failed anthracycline chemotherapy. In a pivotal randomized phase III study of doxorubicin plus docetaxel versus doxorubicin plus cyclophosphamide as first-line chemotherapy for 429 patients with metastatic breast cancer, doxorubicin/docetaxel emerged as the more effective regimen.

Coping with cancer: can exercise help?

A comprehensive review of the recent literature reveals that exercise has a positive effect on a broad range of quality-of-life parameters after patients are diagnosed as having cancer. The general exercise prescription is moderate-intensity exercise, 3 to 5 days per week, 20 to 30 minutes per session. Conditions that warrant prescription modification include fatigue periods during treatment, acute or chronic physical impairments that may have resulted from surgery or adjuvant therapy, and the presence of bone cancer.

Differential transport of cytosine-containing nucleosides by recombinant human concentrative nucleoside transporter protein hCNT1.

The transportability of cytosine-containing nucleosides by recombinant hCNT1 was investigated in transfected mammalian cells. Apparent K(m) values for hCNT1-mediated transport of uridine, cytidine and deoxycytidine were, respectively, 59, 140 and 150 microM. Uridine transport was inhibited 89, 32 and 11%, respectively, by 500 microM gemcitabine, cytarabine and lamivudine, demonstrating that, unlike gemcitabine (a high-affinity hCNT1 permeant), cytarabine and lamivudine are poor hCNT1 permeants.

Genetic studies in neural tube defects. NTD Collaborative Group.

Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families.

A phase II trial of triamcinolone hexacetanide for symptomatic recurrent malignant ascites.

Ascites is a common complication of advanced cancer and frequently requires paracentesis to reduce symptoms of pain, anorexia, and dyspnea. For many patients repeat paracenteses are required at short intervals. We prospectively studied 15 patients with recurrent ascites of malignancy to determine if intraperitoneal triamcinolone hexacetonide, a slowly metabolized corticosteroid, produced objective and symptomatic responses.

Nucleoside transporters of mammalian cells.

In this review, we have summarized recent advances in our understanding of the biology of nucleoside transport arising from new insights provided by the isolation and functional expression of cDNAs encoding the major nucleoside transporters of mammalian cells. Nucleoside transporters are required for permeation of nucleosides across biological membranes and are present in the plasma membranes of most cell types. There is growing evidence that functional nucleoside transporters are required for translocation of nucleosides between intracellular compartments and thus are also present in organellar membranes.

The thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) is not a major risk factor for neural tube defect in American Caucasians. The NTD Collaborative Group.

Mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) have been implicated as a risk factor in the formation of neural tube defects. We investigated this gene in a series of 65 sporadic American Caucasian patients with lumbosacral NTD and their unaffected parents, using both case-control design and assessment of linkage disequilibrium. We found no evidence to support mutations in MTHFR as a significant risk factor for NTD in this population.

Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters.

Background: Gemcitabine, a pyrimidine analogue of deoxycytidine, is an anticancer nucleoside drug that requires functional plasma membrane nucleoside transporter proteins to reach its intracellular targets and cause cytotoxicity. Because of technical difficulties inherent in studying nucleoside transport in human cells, we rigorously defined gemcitabine membrane transportability by producing each of the available human (h) and rat (r) recombinant nucleoside transporters (NTs) individually in Xenopus laevis oocytes.

Methods: Oocytes were microinjected with in vitro-transcribed RNAs derived from complementary DNAs encoding (C = concentrative) rCNT1, rCNT2, hCNT1, hCNT2, (E = equilibrative) rENT1, rENT2, hENT1, and hENT2.

Possible interaction of genotypes at cystathionine beta-synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects. NTD Collaborative Group.

Neural tube defects are a common, complex disorder with genetic and environmental components to risk. We investigated the previously reported interaction between homozygosity for the thermolabile variant at the methylenetetrahydrofolate reductase and heterozygosity for the 844ins68 allele at the cystathionine beta-synthase loci in cases with lumbosacral myelomeningocele and their parents. Using control allele frequencies from our sample pooled with those published in the literature, we confirm a marginally significant interaction at these two loci.