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Biomedical subjects

J Ford

Publications and source records attributed to J Ford.

At least 19 recordsLinked to original sources
PubMed1992

Overexpression of P-glycoprotein and alterations in topoisomerase II in P388 mouse leukemia cells selected in vivo for resistance to mitoxantrone.

The overexpression of P-glycoprotein (PGP) and alterations in DNA topoisomerase II (TOPO II) were evaluated in mouse leukemia P388 cells selected in vivo for mitoxantrone (MTT) resistance (P388/MTT) and compared to doxorubicin (DOX) resistant (P388/DOX) or vincristine (VCR) resistant (P388/VCR) models. Among a panel of TOPO II inhibitors which included etoposide (VP-16), DOX, MTT and 4'-[(9-acridinyl)-amino]methanesulfon-m-anisidide (m-AMSA), the relative resistance compared to parental sensitive P388/S cells was: P388/DOX greater than P388/MTT greater than P388/VCR. All the resistant sublines exhibited minimal cell kill (less than 20%) at vincristine concentrations greater than 100-fold the IC50 for P388/S cells. In a soft-agar colony-forming assay, the modulation of cytotoxicity in P388/MTT cells by the calmodulin inhibitor trifluoperazine following a 3-hr drug treatment demonstrated a marked potentiation in cell kill with MTT, VP-16, DOX and m-AMSA but not VCR. Immunoblotting data revealed that while PGP was not detectable in P388/S cells, the overexpression of PGP was apparent in P388/MTT cells and the relative expression between the resistant sublines was: P388/DOX greater than P388/MTT greater than P388/VCR. Although the amount and DNA cleavage activity of TOPO II in nuclear extracts from P388/VCR cells were comparable to those in P388/S cells, they were markedly lower in both P388/DOX and P388/MTT cells. However, decatenation activity of TOPO II in nuclear extracts was comparable between the sensitive (P388/S) and resistant sublines (P388/MTT, P388/DOX, and P388/VCR). Results from the present study demonstrated that P388 cells selected for resistance to mitoxantrone exhibit changes in TOPO II and overexpression of PGP similar to P388/DOX cells, while vincristine resistant cells only overexpress PGP. Since therapeutic strategies are primarily designed to interfere with PGP-mediated drug efflux, the choice of agents for modulating resistance in tumors which overexpress PGP versus tumors which overexpress PGP with altered TOPO II could be different.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Serum oncoproteins and growth factors in asbestosis and silicosis patients.

Levels of 9 different oncoproteins and growth factors were assayed by immunoblotting with monoclonal antibodies in 91 serum samples collected between March 1983 and August 1987 from 46 pneumoconiosis patients (36 asbestosis, 10 silicosis) at high risk for the development of cancer. Follow-up of these patients through June 1991 showed that 18 had developed cancer (11 lung, 2 pleural mesothelioma, 2 transitional-cell carcinomas of the urinary bladder, 1 osteosarcoma, 1 non-Hodgkin's lymphoma, 1 adenocarcinoma of the gallbladder). Increased serum levels of ras oncogene-related protein (p21) were found in 7 of the 18 patients who developed cancer (5 lung, 2 pleural mesothelioma) versus 2 of the 28 patients without cancer, a statistically significant difference (p = 0.012). In addition, 6 of the 7 p21-positive cancer cases had positive serum samples prior to clinical diagnosis of disease (average = 16.3 months, range = 3-26 months prior to diagnosis), suggesting that elevated serum p21 levels may be a useful marker for earlier detection in a significant percentage of respiratory malignancies. Finally, elevated serum levels of PDGF-related protein were detected significantly more frequently in advanced pneumoconiosis cases (ILO radiographic classification of 2/1 or greater) than in less advanced cases (80% vs. 41.9%; p = 0.016), and there was a tendency for these PDGF-positive patients to have progression of their disease (68.2% vs. 41.7%; p = 0.065), suggesting that elevated serum PDGF levels may be a marker for the development of severe and progressive pneumoconioses.

Aged↗
PubMed1992

Two malignant peripheral primitive neuroepithelial tumor cell lines established from consecutive samples of one patient: characterization and cytogenetic analysis.

A 6-year-old girl presented with a tumor of the right shoulder involving bone, adjacent soft tissue, and regional lymph nodes. The conventional histologic diagnosis was ambiguous, initially suggesting lymphoma. After relapse on lymphoma therapy, reevaluation with additional multiple diagnostic techniques performed on the biopsy tissue and on two cell lines derived from the biopsies established the diagnosis of a primitive neuroepithelial tumor of bone and soft tissue. This was strongly supported by 1) focal rosette formation by the tumor cells and positive immunostaining for neuron-specific enolase and synaptophysin, with absent staining for leukocyte common antigen; 2) at the ultrastructural level, formation of cellular processes containing microtubules, a paucity of neurosecretory granules, absence of synaptic junctions, formation of long "intermediate" junctions between cells, and, in culture, widespread development of rosettes; 3) marked surface positivity to W 6/32 and negativity to HSAN 1.2 antibodies; and 4) elevated expression of MYC and lack of overexpression of MYCN oncogenes. Numerical and structural abnormalities were present in the karyotype, but the expected t(11;22)(q24;q12) was not present in the tumor-involved marrow or in either of the established tumor cell lines, although there was an interstitial deletion of 11q involving breakpoints in q21 and q23.

Biomarkers, Tumor↗
PubMed1992

Needs assessment for persons with severe mental illness: what services are needed for successful community living?

The development and implementation of effective community support systems are goals of many public mental health authorities who are attempting to shift the focus and dollars for mental health services from inpatient to community care. This article presents the results of a survey which asked 90 community mental health agency case managers to assess the community support and residential needs of over 1400 of their clients. Medication monitoring and therapy were rated high priority needs. Psychosocial treatment, day and vocational activities also ranked high. Survey responses regarding residential services indicated a need for more supported and supervised options.

Adolescent↗
PubMed1992

Three neuroblastoma cell lines established from consecutive samples of one patient which show distinct morphologic features, MYCN amplification, and surface marker expression.

Three neuroblastoma cell lines established from tumor samples obtained from one patient are described. The three lines were derived from bone marrow aspirates taken at diagnosis, and 13 and 15 months later. The origin of the cell lines PER-106, PER-107, and PER-108 from malignant neuroblasts was confirmed by electron microscopy studies, surface marker analysis, and assessment of MYCN amplification. Cell lines PER-107 and PER-108, which were established from tumor samples obtained at the time of progressive disease, have significantly shorter doubling times than PER-106 and grow mainly substrate-adherent, while cell line PER-106 (established from sample obtained at diagnosis) consists of small round neuroblastic cells which form large aggregates in suspension culture. The electron microscopy studies revealed distinctive neuroblast-like ultrastructure in all cell lines. The MYCN copy number was amplified (greater than 10 copies) in the established cell lines and in the fresh tumor samples and the relative abundance of MYCN RNA in the cell lines correlated roughly with the extent of the MYCN gene amplification. However, distinct phenotypic differences can be demonstrated among these three lines, which provide a model for the further examination of this highly malignant tumor. Detection of MYCN amplification by chromosomal in situ hybridization was performed on this set of cell lines, as reported by McRobert et al. (this issue, pages 128-134).

Antibodies, Monoclonal↗
PubMed1992

Preliminary results of the use of urinary excretion of pyridinium crosslinks for monitoring metastatic bone disease.

The collagen crosslinks, pyridinoline and deoxypyridinoline, are recently described markers of the rate of bone resorption. The urinary excretion of these compounds, expressed as a ratio to urinary creatinine, has been measured using ion-pair reversed phase high-performance liquid chromatography in 20 patients receiving oral pamidronate for bone metastases from breast cancer. Before treatment the ratio of pyridinoline and deoxypyridinoline to creatinine in urine (UPCR and UdPCR respectively) were each above normal in 16/20 (80%) patients. Urinary calcium excretion (UCCR) was elevated in 15/20 (75%). There was a strong correlation between UPCR and UdPCR, but neither of the crosslink measurements correlated well with UCCR. Urinary excretion of all three indices of bone resorption fell significantly during pamidronate treatment. The median values after 4 weeks treatment were 63% of baseline for UPCR, 45% for UdPCR and 26% for UCCR. From this preliminary study urinary pyridinoline and deoxypyridinoline excretion appear to be promising markers of bone resorption in advanced malignancy. Their role in response assessment and the advantages over UCCR measurements merit further study.

Administration, Oral↗
PubMed1992

Serum growth factors and oncoproteins in firefighters.

Firefighters are potentially at increased risk for cancer and non-malignant respiratory disease due to their toxic exposures on the job. Growth factors and oncogene proteins are thought to play a role in the development of various malignancies and pulmonary fibrotic diseases. Therefore, a cohort of firefighters and matched controls have been screened for the presence of nine different growth factors and oncoproteins using an immunoblotting assay. Fourteen of the firefighters were found to be positive for beta-transforming growth factor (beta-TGF) related proteins compared to no positives in the controls (P = 0.0017). These results suggest that beta-TGF may be a possible biomarker for monitoring firefighters and other exposed workers for the potential development of cancer or non-malignant respiratory disease.

Amino Acid Sequence↗
PubMed1992

Protective epitopes on the fusion protein of respiratory syncytial virus recognized by murine and bovine monoclonal antibodies.

The regions of the fusion protein of respiratory syncytial virus (RSV) that react with neutralizing, fusion-inhibiting and highly protective bovine and murine monoclonal antibodies (MAbs) were mapped by two methods: (i) competitive binding assays and (ii) production and analysis of antibody-escape mutants. Competitive binding assays with 16 murine and 10 bovine MAbs identified 11 antigenic sites on the fusion (F) protein, many of which overlapped extensively, and indicated that cattle, a natural host for RSV, and mice recognize similar epitopes. Neutralizing MAbs identified four sites, two of which were also fusion-inhibiting and highly protective in mice. The pattern of reactivity of antibody-escape mutants with the MAbs confirmed the mapping of the protective epitopes deduced from competitive binding assays. A comparison of the biological properties of MAbs to the F protein indicated that protection against RSV infection correlated with fusion inhibition rather than neutralization titre or complement-dependent lysis of virus-infected cells.

Animals↗
PubMed1991

Effect of the calmodulin inhibitor trifluoperazine on phosphorylation of P-glycoprotein and topoisomerase II: relationship to modulation of subcellular distribution, DNA damage and cytotoxicity of doxorubicin in multidrug resistant L1210 mouse leukemia cells.

The results from the present study using the sensitive and progressively DOX resistant L1210 model system demonstrated that the effects of TFP are not due to redistribution of DOX to the nucleus, and modulation of cytotoxicity is related to effects on DOX-induced DNA strand breaks. Although TFP affects phosphorylation of PGP and TOPO II (R2 greater than R1), the comparable DNA strand breaks at lower DOX levels with TFP in the resistant sublines suggest that modulation of TOPO II function related to drug-induced DNA damage by calmodulin-mediated events may be an important mode of action.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Relationship between expression of P-glycoprotein and efficacy of trifluoperazine in multidrug-resistant cells.

Tumor cell resistance due to enhanced efflux of drugs with diverse structures and/or mechanisms of action is termed multidrug resistance (MDR), and modulation of the MDR phenotype by calcium blockers or calmodulin inhibitors is suggested to involve P-glycoprotein. In drug-sensitive (S) and 5-fold doxorubicin (DOX)-resistant (R0) L1210 mouse leukemia cells, no obvious differences in mdr mRNA or P-glycoprotein expression or alterations in cellular uptake, retention, or cytotoxicity of vincristine (VCR) were observed. However, in the 10-fold (R1) and 40-fold (R2) DOX-resistant sublines, expression of P-glycoprotein was correlated with the level of resistance (R2 greater than R1). An RNase protection assay revealed that elevated levels of mdr1 and mdr2 mRNA were detected in R1 and R2 cells, with an additional increase in mdr3 mRNA in the R2 subline. Further, in the R1 and R2 sublines, no VCR dose-dependent cytotoxicity was apparent, and cell kill of greater than 40% was not achievable following a 3-hr drug exposure. Cellular uptake and retention of VCR were 2- to 4-fold lower in the R1 and R2 sublines, compared with similarly treated S or R0 cells. Potentiation of VCR cytotoxicity by a noncytotoxic concentration of 5 microM trifluoperazine (TFP) was greater than 2-fold in S and R0 cells and less than 1.3-fold in the R1 and R2 sublines. Modulation of VCR uptake by 5 microM TFP in the S and R0 cells was 2-fold and it was 4- to 7-fold in the R1 and R2 sublines. The presence of 5 microM TFP, by competing for efflux, enhanced VCR retention 1.5-fold in S and R0 cells and 2- to 4-fold in the R1 and R2 sublines. In contrast to these results with VCR, dose-dependent cytotoxicity of DOX was apparent in all the resistant sublines, and modulation of DOX cytotoxicity by 5 microM TFP was dependent on the level of resistance. Cellular accumulation of DOX was 20 and 50% lower in the R1 and R2 sublines, respectively, compared with similarly treated S or R0 cells. Marked increases (greater than 1.5-fold) in cellular accumulation of DOX by TFP were apparent only in the R2 subline. Results suggest that a relationship between overexpression of P-glycoprotein isoforms and their role in affecting cellular drug levels and consequent cytotoxicity in MDR L1210 cells determines resistance to VCR but not DOX.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Treating hard-to-treat tuberculosis patients in Massachusetts.

For most patients with tuberculosis (TB), treatment has never been shorter or cure more certain than with current drug regimens. However, in Massachusetts and elsewhere in the United States there is a growing minority of patients who are not easily cured with the best available outpatient regimens. Close treatment supervision through culturally appropriate outreach workers has been successful for some foreign-born TB patients in whom therapy might otherwise fail. Full supervision of outpatient therapy, sometimes with incentives, has also been used successfully to treat selected homeless patients. However, a growing number of hard-to-treat homeless patients are addicted to illicit drugs, human immunodeficiency virus (HIV) infected, or have major behavioral problems. These patients often do not cooperate with fully supervised therapy and acquire drug resistance as a result of erratic drug taking. They can then transmit these dangerous organisms to others, especially to other HIV-infected persons within shelters, jails, prisons, detoxification centers, clinics, and hospitals, infecting institutional workers at the same time. In Massachusetts these hard-to-treat TB patients are increasingly being legally committed to involuntary, long-term, inpatient therapy. Although long-term inpatient TB treatment is expensive, it is likely to be cost effective when it successfully breaks the chain of transmission within institutions, and achieves cures not otherwise possible. A new model of lower-cost inpatient care that incorporates psychosocial rehabilitation techniques to modify the behavior of the hardest-to-treat patients is briefly described. Ultimately, however, the reversal of the current upsurge in hard-to-treat TB cases in Massachusetts and elsewhere depends not on inpatient care but on substantial changes in the socioeconomic order that perpetuates homelessness, substance abuse, crime, and the transmission of both TB and HIV infections.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Trifluoperazine modulation of resistance to the topoisomerase II inhibitor etoposide in doxorubicin resistant L1210 murine leukemia cells.

Murine leukemia L1210 cells selected for progressive resistance to doxorubicin (DOX) display both the multidrug resistant (MDR) phenotype and reductions in drug induced topoisomerase II-mediated DNA cleavage in nuclear extracts (Ganapathi, R.; Grabowski, D.; Ford, J.; Heiss, C.; Kerrigan, D.; Pommier, Y., Cancer Commun. 1:217-224; 1989). The present study was performed to characterize the results of exposure of the sensitive (S) and progressively DOX-resistant (10-fold, R1, and 40-fold, R2) L1210 cells to the topoisomerase II inhibitor, etoposide, and to investigate the modulating effects of the calmodulin inhibitor, trifluoperazine (TFP). Immunoblotting experiments indicated no apparent decrease in the p170 or p180 isoforms of topoisomerase II in the resistant sublines versus parental sensitive cells. Cross-resistance to etoposide (VP-16) was similar to that of DOX (10- and 40-fold). A non-cytotoxic concentration of 5 microM TFP enhanced cell kill 1.5- fold in the sensitive and 3- to 5-fold in the progressively DOX-resistant cells. Accumulation of VP-16 was 30% to 50% lower in the resistant sublines versus similarly treated sensitive cells, and a marked enhancement of drug uptake in the presence of TFP was observed in the sensitive but not in the resistant cells exposed to equivalent extracellular levels of VP-16. Although equimolar concentrations of VP-16 produced fewer DNA single strand breaks (SSB) and DNA protein crosslinks (DPC) in the resistant versus sensitive cells, similar DNA damage was apparent when S and R1, but not R2, cells were treated at VP-16 concentrations that produced equivalent cell death.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗