PubMed Health⌕ Search

Biomedical subjects

R C Ribeiro

Publications and source records attributed to R C Ribeiro.

At least 91 records · Page 5Linked to original sources
PubMed1996

Thyroid hormone activation of transcription is potentiated by activators of cAMP-dependent protein kinase.

We characterized the cross-talk between activators of protein kinase A (PKA) and thyroid hormone (T3) in T3 receptor (TR)-mediated transcription. U937 cells were cotransfected with a plasmid expressing the TR and a reporter plasmid containing a T3 response element (TRE) oriented either as a direct repeat or as a palindrome upstream of the thymidine kinase promoter linked to the chloramphenicol acetyltransferase gene. T3 activated transcription by 10-fold. T3 response was potentiated 2.5-3-fold by activators of PKA, but an activator of protein kinase C or of guanylate kinase was ineffective. In the absence of T3, activators of PKA had no effect on transcription. TR heterodimerization with the retinoid X receptor may facilitate T3/PKA cross-talk because coexpression of the retinoid X receptor potentiated cross-talk. Synergy was not observed in JEG-3, F9, CV-1, HeLa, L929, and HTC cells, indicating that it may require cell-specific factors. Synergy required the DNA- and ligand-binding domains, but not the amino-terminal domain, indicating that T3- and TRE-induced conformational changes on the TR are essential for cross-talk. PKA phosphorylated the TR in vitro, suggesting that, like other nuclear receptors, the TR is a target for PKA. These results imply that PKA cross-talks with T3 at the level of the TRE-bound TR, enhancing its transcriptional activity in a cell-specific manner.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia.

Relapsed acute lymphoblastic leukemia (ALL) usually carries a dire prognosis. We evaluated the effectiveness and long-term complications of intensive rotational combination chemotherapy for late hematologic relapse (median, 16 months after elective cessation of therapy) among 34 children and young adults (ages 4 to 23 years). Concurrent central nervous system (CNS) relapse was present in 3 cases and testicular relapse in 4. Secondary therapy comprised an intensive five-drug reinduction (6 weeks) followed by continuation treatment with four drug pairs, rotated weekly in 4-week cycles over 120 weeks. Intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine) was given three times during reinduction and every 8 weeks during continuation. Treatment was electively discontinued at week 120 in the absence of detectable disease. Thirty-three patients (97%) attained a second complete remission. At a median follow-up of 9.3 years (range, 4.5 to 11.4), estimates of 5-year second event-free and overall survival (+/- SE) are 65% +/- 8% and 79% +/- 7%, respectively. Eleven patients had a second relapse (9 marrow, 2 testicular) and one developed secondary myeloid leukemia. There have been no CNS relapses or deaths in remission. Treatment was well-tolerated and was given largely on an outpatient basis. Late effects are primarily endocrinologic; one child had a second malignant solid tumor (presumed related to initial radiation therapy) that was treated successfully. Intensive treatment with alternating non-cross-resistant drug pairs for late hematologic relapses of ALL is effective and well-tolerated, and produces results similar to those achieved in patients with newly diagnosed ALL. Event-free survival compares favorably with reports of other relapse regimens, including those incorporating bone marrow transplantation.

Adolescent↗
PubMed1996

Thyroid hormone export regulates cellular hormone content and response.

Actions of thyroid hormones (THs) are determined by intracellular free hormone concentration. Here we report that enhanced TH extrusion via a saturable, cold-sensitive mechanism lowers intracellular TH and causes TH resistance in hepatoma cells. Since these cells overexpress multidrug resistance P-glycoproteins and TH extrusion and resistance are blunted by verapamil, P-glycoproteins may mediate this resistance. Verapamil-inhibitable TH efflux was also found in primary hepatocytes, cardiocytes, and fibroblasts. These findings demonstrate that TH extrusion can modulate TH availability and action in mammalian cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Wiskott-Aldrich syndrome in a family with Fanconi anemia.

Thrombocytopenia may be the presenting finding for both Wiskott-Aldrich syndrome and Fanconi anemia. We examined a sibship of four boys who had features of both of these hematologic disorders. Peripheral blood lymphocytes from three of the boys demonstrated DNA instability when cultured with diepoxybutane, confirming the diagnosis of Fanconi anemia in these patients. However, results of linkage analysis and X chromosome inactivation studies were consistent with the diagnosis of Wiskott-Aldrich syndrome in two of the boys, including one of the boys with Fanconi anemia. These findings could be attributed to the occurrence of two rare genetic disorders in a single family or to an unusual variant of Fanconi anemia. The recent identification of the Wiskott-Aldrich gene permitted us to address this question directly. Epstein-Barr virus-transformed cell lines from the two boys thought to have Wiskott-Aldrich syndrome on the basis of linkage analysis failed to express transcripts for the Wiskott-Aldrich gene. Genomic DNA from these two patients demonstrated a G insertion in the tenth exon of the Wiskott-Aldrich gene, resulting in a frameshift and a premature stop codon. Surprisingly, the patient with Fanconi anemia and a null mutation in the Wiskott-Aldrich gene had typical Fanconi anemia but mild Wiskott-Aldrich syndrome.

Child↗
PubMed1996

Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia.

PURPOSE: Although epipodophyllotoxins are commonly used in contemporary treatment regimens for acute lymphoblastic leukemia (ALL), their potential role in CNS-directed therapy has received little attention. We prospectively studied 20 children during initial remission of ALL and 16 children at relapse to assess CSF penetration of etoposide. METHODS: Simultaneous plasma and CSF concentrations were assessed at a median of 2.8 hours (range, 0.4 to 5.3) after an intravenous (i.v.) or oral dose in 41 paired samples. RESULTS: Etoposide given at 300 mg/m2 i.v. to patients during first remission and at 50 or 25 mg/m2 orally to those in relapse resulted in median CSF levels of 0.175 mumol/L (range, .066 to 2.12), 0.011 mumol/L (range, .004 to .032), and 0.007 mumol/L (range, .003 to .014), respectively. The CSF etoposide concentration was > or = 10 nmol/L in 20 of 20, five of 10, and two of 11 courses following 300 mg/m2 i.v., 50 mg/m2 orally, and 25 mg/m2 orally, respectively, and was positively related to both the concurrent etoposide plasma concentration (R2 = .64) and to dose (R2 = .73). The median ratio of CSF to plasma concentration was 0.30% (range, 0.09% to 3.12%), which was not related to dose, plasma concentration, or time postdose at which samples were obtained, but was positively correlated with the CSF protein concentration (R2 = 0.43, P = .006). Both the absolute etoposide CSF concentrations (P = .008) and the ratio of CSF to plasma concentrations (P = .023) were higher among first-remission patients who had CSF leukemic blasts at diagnosis compared with those without CSF blasts. CONCLUSION: Because etoposide concentrations as low as 10 nmol/L may be cytotoxic in vitro, prolonged daily oral low-dose (50 mg/m2) or conventional i.v. doses of etoposide may contribute to successful CNS-directed therapy in children with ALL.

Administration, Oral↗
PubMed1996

St Jude Children's Research Hospital's International Outreach Program.

Over 80% of children with cancer live in developing countries, where access to medical services is limited to varying degrees. In many of these countries, economic conditions and general health care have improved sufficiently to permit the development of more sophisticated medical services. The introduction of pediatric oncology programs becomes appropriate as deaths from malnutrition and infections decrease and cancer emerges as an important cause of childhood mortality. In the absence of such services, the worldwide war against pediatric cancer will ultimately be lost because of the rapidly growing pediatric populations in developing countries that now lack the facilities and expertise to treat childhood malignancies. We believe that the development of pediatric cancer centers in many of these countries is both appropriate and feasible. Partnerships in which established pediatric oncology centers work with the governments and private sectors of developing nations to implement key facilities are an efficient and cost-effective way to introduce such services. The challenges of these outreach efforts are significant -- as are the expected benefits.

Brazil↗
PubMed1996

Prognostic factors in the acute lymphoid and myeloid leukemias of infants.

The age boundaries and prognostic factors that define the infant leukemias are still controversial. We therefore analyzed event-free survival according to age group in 96 children treated for acute lymphoblastic leukemia (ALL) and 51 treated for acute myeloid leukemia (AML) before the age of 2 years. The study population was registered in consecutive institutional trials of multiagent chemotherapy conducted between 1980 and 1994. Among infants with ALL, event-free survival was significantly poorer in the 0- to 6-month-old group than in patients treated between 6 and 12 months of age (P = 0.03), whose outcome was in turn inferior to that in the 12- to 18-month and 18- to 24-month age groups (P = 0.013). Leukemic cells from ALL patients younger than 12 months had a significantly higher frequency of 11q23/MLL abnormalities, as well as better growth in stromal cell culture, compared to lymphoblasts from the older groups (P < 0.01). The only independent predictor of adverse prognosis among infants diagnosed with ALL before age 12 months was the presence of an 11q23/MLL rearrangement (P = 0.03). These findings contrast sharply with results for the AML cohort, whose event-free survival did not vary significantly by age group (P = 0.58). Male sex (P = 0.01) and leukocyte count > or = 50 x 10(9/l) (P = 0.04), but not 11q23 abnormalities, were independently associated with a poorer outcome for children with AML younger than 12 months at diagnosis. Thus, in very young children with ALL (but not AML), the rearrangement status of the 11q23/MLL region supersedes age group as a determinant of treatment outcome.

Age Factors↗
PubMed1995

Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine.

BACKGROUND: Infection with the human T-cell lymphotropic virus type I, a retrovirus, can cause a distinctive cancer, adult T-cell leukemia-lymphoma. The median survival of patients with the acute and lymphomatous forms of the disease is short, despite the use of cytotoxic chemotherapy. METHODS: We treated 19 patients with acute or lymphomatous forms of adult T-cell leukemia-lymphoma with oral zidovudine (200 mg five times daily) and interferon alfa (Intron A, 5 to 10 million units subcutaneously each day). Seven of these patients had either relapsed after multiagent cytotoxic chemotherapy or failed to respond to that treatment. RESULTS: Major responses were achieved in 58 percent of the patients (11 of 19), including complete remission in 26 percent (5 of 19). Four patients in whom prior cytotoxic therapy had failed had major responses, two of which were complete remissions. Six patients have survived for more than 12 months, with the longest remission since the discontinuation of treatment lasting more than 59 months. CONCLUSIONS: The combination of zidovudine and interferon alfa has activity against adult T-cell leukemia-lymphoma, even in patients in whom prior cytotoxic therapy has failed. This regimen should be evaluated further for its role in the treatment of adult T-cell leukemia-lymphoma.

Adolescent↗
PubMed1995

Unusual cutaneous toxicity following treatment with dactinomycin: a report of two cases.

Dactinomycin-induced cutaneous toxicity is rare in pediatric patients not receiving radiation therapy. We describe dactinomycin-related lesions in the axilla, groin, and central line exit site of two children treated for rhabdomyosarcoma, neither of whom had received radiation treatment. One patient was initially treated with systemic antifungal therapy, and developed recurrent lesions on reexposure to the drug. The other was noted to have mild, diffuse hyperpigmentation. Skin biopsies revealed interface dermatitis with syringometaplasia in both cases. Both children recovered uneventfully within 4 weeks. Recognition of unusual rashes with a characteristic distribution in patients receiving dactinomycin should aid in diagnosis, and help avoid unnecessary therapeutic procedures.

Child↗
PubMed1995

Veno-occlusive disease of the liver after chemotherapy for rhabdomyosarcoma: case report with a review of the literature.

We describe the case of a 3-year-old girl who developed veno-occlusive disease of the liver while receiving chemotherapy for parameningeal rhabdomyosarcoma. After suffering lethargy and oral mucosal bleeding for one day, the patient exhibited a sudden weight gain and refractoriness to platelet transfusions. Symptoms rapidly worsened with elevation of liver enzymes, bleeding diatheses, and respiratory failure. An ultrasound scan of the liver demonstrated reversed flow in the portal vein. Maximal supportive care, including tracheal intubation and mechanical ventilation, was required. The patient gradually recovered with no respiratory and minimal neurological sequelae. Veno-occlusive disease of the liver should be considered in children receiving chemotherapy who develop weight gain, a sudden drop in platelet count and derangement of liver enzymes. Aggressive supportive measures should be instituted if necessary, as patients surviving the acute phase can expect to make a full recovery.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Pharmacokinetics and pharmacodynamics of 21-day continuous oral etoposide in pediatric patients with solid tumors.

PURPOSE: The objectives of this study were to determine etoposide pharmacokinetics during continuous low-dose oral administration to children with solid tumors and to evaluate the relationships between parameters of etoposide systemic exposure and toxicity. PATIENTS AND METHODS: In this phase I study, children were administered oral etoposide (25 to 75 mg/m2/day) for 21 days as a diluted solution of the intravenous preparation, divided into three equal daily doses. Plasma pharmacokinetics were studied on day 1 of therapy in 18 children and again on day 21 in 14 of these children. Etoposide plasma concentration-time data were fitted to a first-order absorption, two-compartment model with use of bayesian estimation. Pharmacokinetic parameter estimates from day 1 were used to estimate steady-state etoposide systemic exposure in all children. Stepwise multivariate regression was used in an exploratory manner to determine patient, laboratory, or pharmacokinetic predictors of toxicity. RESULTS: Although there was substantial intrapatient variability, there was no difference in the area under the concentration-time curve [AUC(0-8hr)] measured at day 21 compared with the steady-state AUC(0-8hr) estimated from day 1 pharmacokinetic parameters (p = 0.64). Degree of neutropenia was best predicted by the estimated duration that steady-state plasma etoposide concentrations were maintained above 1 microgram/ml (t > 1 microgram/ml) rather than peak plasma concentrations, AUC(0-8hr), dosage, or other patient characteristics. Assuming a bioavailability of the oral solution of approximately 50%, the median etoposide systemic clearance was 21.4 ml/min/m2, a value similar to clearance estimates after intravenous etoposide in pediatric populations. CONCLUSION: We conclude that a parameter reflective of etoposide systemic exposure (t > 1 microgram/ml) correlates more strongly with neutropenia than does dosage or other patient characteristics.

Administration, Oral↗
PubMed1995

The nuclear hormone receptor gene superfamily.

The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.

Endocrine System Diseases↗
PubMed1995

An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia.

PURPOSE: To assess the salvage rate and long-term complications among children treated with an intensive regimen for isolated CNS relapse during first remission of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twelve boys and eight girls, diagnosed at a median age of 4 years, had CNS relapse at a median age of 7 years. Five had CNS leukemia at presentation, while five completed treatment before relapse. First complete remission lasted a median of 22.5 months. Ten patients had received cranial irradiation plus intrathecal (IT) therapy, and the remainder had received high-dose intravenous and/or IT methotrexate (MTX) as CNS-directed treatment. Retrieval therapy consisted of a five-agent intensive reinduction regimen followed by continuation therapy with four rotating drug pairs. Triple-IT therapy was administered weekly for 4 to 5 weeks, then every 6 weeks until craniospinal radiation (cranium, 24 Gy; spine, 15 Gy; both sites, 1.5 Gy per fraction) was administered. RESULTS: All 20 children achieved a second complete remission. The 5-year estimate of disease-free survival (mean +/- SE) was 70% +/- 11%. Thirteen patients remain in remission at 71+ to 126+ months (median, 104+), and 10 of 13 patients tested have normal IQ scores. Four patients have had a second relapse (one CNS and three non-CNS), and three have developed other malignancies. Prior cranial irradiation was associated with subsequent failure; only three of 10 patients who previously received radiotherapy, compared with all of the other 10 patients, remained in second remission. CONCLUSION: This intensive retrieval therapy is effective and well tolerated by children with an isolated CNS relapse of ALL, especially those who have not received prior cranial irradiation. Most patients have no significant neuropsychologic impairment.

Adolescent↗
PubMed1995

L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins.

The risk for induction of epipodophyllotoxin-related acute myeloid leukemia (AML) depends largely on the schedule of drug administration and, to a lesser degree, the cumulative dose. Concomitant use of other genotoxic drugs, such as alkylating agents and cisplatin, can increase the hazard further. We have treated 154 consecutive higher-risk cases of acute lymphoblastic leukemia in our recent Total Therapy Study XIII with an intensive post-remission regimen of chemotherapy that included etoposide given every other week or less often-a schedule associated with a relatively low cumulative incidence of secondary AML in our Study XI. Unexpectedly, four patients have developed secondary AML at 12 to 23 months from the start of treatment (median, 16 months). The 2-year cumulative risk estimate significantly exceeds that for 185 historical controls in Study XI whose continuation regimen included epipodophyllotoxins every other week: 5.4% (95% confidence interval, 0-11%) compared with 1.1% (0-2.6%), P = 0.046. Compared to patients treated in Study XI, those enrolled in Study XIII receive fewer scheduled doses of epipodophyllotoxin (48 (all etoposide) vs 63 (30 etoposide, 33 teniposide)) but 16 to 19 additional doses of L-asparaginase and eight additional doses of high-dose methotrexate, all within the week preceding etoposide treatment. We attribute the apparently increased rate of secondary AML in Study XIII to the use of L-asparaginase immediately before etoposide administration. On this schedule, the enzyme could increase systemic exposure to etoposide or its catechol metabolites and reduce the ability of cells to repair DNA damage.

Acute Disease↗