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P Coccia

Publications and source records attributed to P Coccia.

At least 19 recordsLinked to original sources
PubMed1992

O6-Alkylguanine-DNA alkyltransferase content in synchronised human cancer cells.

The DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT) was analysed in the human ovarian-cancer SW626 cell line and in the human promonocytic leukemia U937 cell line following their synchronisation with low non-toxic concentrations of methotrexate. In SW626, AT increased in the early S phase of the cell cycle and then declined during progression of the S phase to levels found in the G1 phase of unsynchronised cells. In contrast, at the G1/S-phase boundary and in the S phase, U937 cells showed a lower AT content than did exponentially growing unsynchronised cells. In addition, AT activity was greatly reduced in resting U937 cells but was not reduced appreciably in resting SW937 cells but was not reduced appreciably in resting SW626 cells. The results of these studies indicate that AT fluctuations do not follow a constant pattern during the cell cycle of different cell lines.

Cell Cycle↗
PubMed1992

O6-alkylguanine DNA alkyltransferase is induced by human recombinant interferon-alpha A/D in mouse liver.

Treatment of C57Bl or BALB/C mice with human interferon-alpha A/D (HuIFN-alpha A/D) significantly increased hepatic levels of the DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AT). The maximum induction was seen 24 h after a single dose of 50-100 micrograms/kg IFN-alpha A/D. No induction was observed in rat liver hepatocytes cultured in vitro. Liver AT was also induced by poly(I:C), which is a potent IFN inducer. By increasing AT levels, IFN could protect against the potentially mutagenic alkylation at guanine O6 position caused by some carcinogens. Moreover this finding suggests a link between immune response and the DNA repair system, possibly acting in concert to defend the body from potentially toxic compounds.

Animals↗
PubMed1991

Lymphomatous presentation of childhood acute lymphoblastic leukemia. A subgroup at high risk of early treatment failure.

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, E-rosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/microliters, male predominance, and older age. This type of presentation of ALL is referred to as the "lymphoma syndrome" (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E-rosette-positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease-free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

Adolescent↗
PubMed1990

Interferon inducers increase O6-alkylguanine-DNA alkyltransferase in the rat liver.

We investigated whether treatment with the interferon inducer polyinosinic-polycytidylic acid and other cytokines (interleukin-1, tumor necrosis factor) or the cytokine inducer lipopolysaccharide modified O6-alkylguanine-DNA alkyltransferase (AT) in rat liver. AT levels were determined in liver extracts using N-[3H]methyl-N-nitrosourea alkylated calf thymus DNA as substrate and an HPLC procedure to measure O6-methylguanine. Doses as low as 0.1 mg/kg i.p. of polyinosinic-polycytidylic acid caused a highly significant increase (P less than 0.01) in AT levels in the liver, evident either 24 or 48 h after treatment. Lipopolysaccharide at the dose of 80 micrograms/kg i.p. also induced AT whereas interleukin-1 (60 micrograms/kg) or tumor necrosis factor (60 micrograms/kg) were inactive. Treatment with human recombinant interferon alpha A/D caused a highly significant increase in AT levels, thus confirming the hypothesis that interferon was probably responsible for the observed effect. These results suggest a link between the immune response and DNA repair mechanisms.

Animals↗
PubMed1990

High-dose N,N',N"-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: phase I studies.

N,N',N''-triethylenethiophosphoramide (thiotepa) is a polyfunctional alkylating agent similar in structure to nitrogen mustard. Thiotepa (synthesized by American Cyanamid Company, Wayne, NJ) underwent clinical trials in the 1960s that showed that it was active against a wide variety of tumors. At a standard dose level (10 to 30 mg/m2), the dose-limiting toxicity is myelosuppression; other toxicities are infrequent. Therefore, high-dose phase I evaluation was encouraged by these observations. Approximately 217 patients have been treated with single-agent high-dose thiotepa administered intravenously daily over 2 hours for 3 days followed by hematopoietic stem cell rescue to prevent prolonged myelotoxicity. The total doses administered ranged from 135 to 1,575 mg/m2. As anticipated, myelotoxicity was substantial, with 180 mg/m2 being the highest dose not requiring stem cell rescue to ensure hematopoietic recovery. Extramedullary toxicities consisted of stomatitis, dermatitis, hepatoxicity, and central nervous system (CNS) toxicity. CNS toxicity was dose-limiting; other toxicities were problematic, ie, dose-dependent but not truly dose-limiting. The maximal tolerated dose of thiotepa is 900 to 1,125 mg/m2, with the lower dose being the maximal dose for evaluation in combination chemotherapy. In high-dose phase I evaluation, the overall response rate was approximately 50% with responses seen in a wide variety of solid tumors, lymphomas, and pediatric tumors. High-dose thiotepa appears to be an alkylating agent with broad-spectrum antitumor efficacy, which should add to the cytoreductive regimens for both solid and hematopoietic tumors.

Bone Marrow Transplantation↗
PubMed1989

Origin of leukemic relapse after bone marrow transplantation: comparison of cytogenetic and molecular analyses.

Leukemic relapse following bone marrow transplant (BMT) is generally due to the recurrence in recipient cells, but may rarely occur as a result of donor cell transformation. Donor cell relapse is generally identified using cytogenetic markers such as the sex chromosomes. Recently, molecular techniques have been used to identify the origin of bone marrow cells by their DNA restriction fragment length polymorphisms. We describe the case of a male pediatric patient who had a leukemic relapse 30 months following BMT from his sister. Both cytogenetic and molecular techniques were used to identify the origin of the leukemic relapse. Cytogenetic analyses indicated the absence of the Y chromosome and the presence of a donor cell type 9qh polymorphism, suggesting a donor cell relapse. Molecular analyses also indicated the absence of the Y chromosome but demonstrated the recurrence of recipient DNA markers from three other chromosomes, suggesting a recipient cell relapse. While the leukemic cell lineage cannot be definitively assigned in this case, our results suggest that caution must be exercised when assigning leukemic cell lineage following post-BMT relapse.

Bone Marrow↗
PubMed1989

Relationship between changes in alveolar surfactant levels and lung defence mechanisms.

Pulmonary surfactant, besides its mechanical properties, is thought to be involved in lung defence mechanisms. We previously described that: (1) in healthy animals, surfactant synthesis stimulation with ambroxol was accompanied by alveolar macrophage activation and a shift of the alveolar elastase/antielastase balance towards increased antielastase activity, and (2) in bleomycin-treated rats alveolar phospholipidosis was obvious 14 days after drug administration, ambroxol protection reduced the phospholipid peak and the morphological apperance of lung fibrosis at the 14th day of the experiment. The present study found that: (1) in healthy rats, the ambroxol-induced increase of alveolar antielastase activity did not appear due to reactivation of alpha 1-antitrypsin normally oxidized in the alveolar milieu; (2) in bleomycin-induced pulmonary fibrosis, ambroxol protection reduced total long collagen content at day 28, and (3) in paraquat-induced pulmonary fibrosis, alveolar phospholipids were markedly reduced throughout the 21 days of the experiment. On increasing the dose of paraquat, ambroxol protection significantly reduced the animals' death rate.

Ambroxol↗
PubMed1988

Liver DNA alkylation after a single carcinogenic dose of dimethylnitrosamine to newborn and adult CFW Swiss mice.

N-nitrosodimethylamine N-demethylase activity, DNA alkylation, capacity for O6-methylguanine repair and cell proliferation were measured in livers of newborn and adult CFW mice after a single carcinogenic dose of DMNA. DNA alkylation was found in newborn and adult mouse livers but it was significantly higher in the newborn. 6- and 7-methyl substitutions of guanine were identified by HPLC analysis in newborn and in adult mouse livers. Metabolic 14C incorporation into adenine and guanine was observed only in liver DNA of newborns. O6-methylguanine levels were higher in newborn than adult mice after a single i.p. dose of [14C]DNMA. Liver DNA repair capacity measured as O6-meG-DNA methyltransferase was higher in adults than in newborns. De novo liver DNA synthesis was more inhibited by DMNA pretreatment in newborn than in adult mice. The relationship between these parameters and the greater neonatal liver tumor susceptibility is discussed.

Alkylation↗
PubMed1987

Central nervous system (CNS) prophylaxis in children with low risk acute lymphoblastic leukemia (ALL).

Five hundred four children with low risk acute lymphocytic leukemia (previously untreated, age 3 to 6 years with white blood counts less than 10,000/mm3 at diagnosis) were randomized into two different central nervous system prophylaxis regimens. One regimen (250 patients) consisted of cranial radiation and intrathecal methotrexate (IT MTX). The second regimen (254 patients) consisted of IT MTX only. Median follow-up time for surviving patients is currently 54 months from randomization. Life table analysis of central nervous relapse, marrow relapse, disease-free survival, and survival shows very similar outcome for both treatment groups. The results indicate that maintenance IT MTX as described in this report can be substituted for cranial radiation in children with low risk ALL.

Central Nervous System↗
PubMed1986

Analysis of prognostic factors in acute lymphoblastic leukemia.

Children with ALL who have a high probability of excellent response, long-term survival, and cure when treated with widely available standard therapy can be identified at the time of diagnosis. Others can be identified who are at high risk of failure to respond, early relapse, and death. The importance of such prognostic characteristics is so great that they should be considered in the selection of appropriate treatment for each patient. Prognostic factors also must be considered in the design and analysis of clinical trials. All prognostic factors are not equally significant and many of them are closely associated. It is possible to rank them in importance and usefulness by appropriate statistical methods. As additional prognostic factors are identified, and as more effective and more specific therapies are developed, the relative importance of prognostic factors will change.

Adolescent↗
PubMed1986

The staging of childhood acute lymphoblastic leukemia: strategies of the Childrens Cancer Study Group and a three-dimensional technic of multivariate analysis.

In childhood acute lymphoblastic leukemia, univariate analyses have identified more than thirty clinical and laboratory prognostic factors. Multivariate analysis is used to sort out the most independent and predictive of these factors, but the methods used are mathematically and conceptually complex. In this report, we depict the interactions between multiple variables graphically using 3-dimensional data displays. This approach helps conceptualize the multivariate process and provides an alternative method. We applied the method to the 2,987 children in the CCG-160 series of studies, and specifically to the "high-risk" subgroups: initial white cell count (WBC) greater than 50,000/microliter; white count greater than 50,000/microliter in conjunction with a mediastinal mass; age at diagnosis less than 1 year; and, central nervous system (CNS) leukemia at diagnosis. Analyzed in this fashion, T-cell immunophenotype, the presence of a large mediastinal mass, CNS leukemia, and the lymphomatous pattern lose their prognostic value when outcome is stratified by age and WBC. The 3-dimensional method confirms the mathematical analyses and provides graphic evidence for the conclusions.

Age Factors↗
PubMed1986

Biochemical characterization of the hepatic effects in mice and rats of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a hepatic neoplasm promoter.

The biochemical effects on the liver of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), a phenobarbital-like enzyme inducer, were studied in the mouse and rat. In mice a single dose of TCPOBOP (3 mg/kg, ip) caused marked and long-lasting (at least 7 days) induction of liver cytochrome P-450, 7-ethoxycoumarin-O-deethylase, and epoxide hydrolase. TCPOBOP had much less effect in rats than in mice, even at a higher dose (30 mg/kg) TCPOBOP also induced DNA synthesis in mice and rats but ornithine decarboxylase activity only in mice. In addition, in mice but not in rats, TCPOBOP increased microsomal membrane fluidity, as detected by fluorescence polarization measurements.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease).

In 1984, simultaneous outbreaks of aplastic crisis and erythema infectiosum occurred in northeastern Ohio. Sera were analyzed from 26 patients with aplastic crisis: 24 had IgM specific for parvovirus B19, five had B19-like particles by electron microscopy, and 13 had DNA from B19; no sera from 33 controls had evidence of recent infection with B19 (P less than .0001). DNA from B19 was also detected in specimens of throat gargle and urine from two patients with aplastic crisis. Sera from 36 of 51 children with erythema infectiosum had B19-specific IgM, compared with serum from one of 42 susceptible controls (P less than .0001). DNA from B19 was detected in sera from only two of 51 patients who had erythema infectiosum. The secondary attack rates among susceptible contacts decreased with age (overall total, 49.6%). Differential rates of asymptomatic infection were observed among black (68.8%) and white (20.0%) household members (P = .003). These were the first identified simultaneous outbreaks of aplastic crisis and erythema infectiosum. Their occurrence provided an opportunity to study the epidemiology and spectrum of B19 infection with geographically and temporally matched comparison groups; our results support the hypothesis that infection with parvovirus causes these two clinical entities.

Adolescent↗
PubMed1979

L-asparaginase-induced hypocomplementemia in acute lymphocytic leukemia (ALL) of childhood.

Serum complement studies were carried out in five children with acute lymphocytic leukemia. During therapy with L-asparaginase, prednisone and vincristine, hypocomplementemia developed in all patients, and disappeared within 2 weeks after the discontinuation of L-asparaginase. Complement breakdown products were not present in plasma. The changes of serum complement levels paralleled those of plasma fibrinogen. These findings suggest that the hypocomplementemia observed in these patients may be related to impaired protein synthesis induced by L-asparaginase.

Adolescent↗