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Biomedical subjects

S Broder

Publications and source records attributed to S Broder.

At least 37 records · Page 2Linked to original sources
PubMed1994

Interleukin-10 suppresses human immunodeficiency virus-1 replication in vitro in cells of the monocyte/macrophage lineage.

The cytokine interleukin-10 (IL-10) has been implicated in the pathogenesis of a number of disease states, including Epstein-Barr virus and human immunodeficiency virus (HIV-1) infections. In the acquired immunodeficiency syndrome (AIDS), it has been suggested that IL-10 may have a deleterious effect by suppressing cell-mediated immunity. However, there are few data on its direct effects on HIV-1 replication. In the present study, we have found that recombinant human IL-10 (rhIL-10), present during days 0 through 2, potently inhibits HIV production in elutriated monocyte/macrophage (M/M) cultures with a 50% inhibitory concentration (IC50) of approximately 0.03 U/mL. This effect did not appear to be caused by toxicity to M/M because there was no change in cell viability, ability to phagocytose latex beads, or protein synthesis as measured by [3H]-leucine incorporation, at doses of rhIL-10 that inhibit viral replication. In addition, lipopolysaccharide-induced production of IL-1 beta, IL-6, or tumor necrosis factor-alpha was not affected at these doses, nor were human mononuclear cell proliferative responses to phytohemagglutinin, OKT3 antibody, or tetanus toxoid. HIV-1 replication was similarly decreased by rhIL-10 in the monocytoid line U937 without signs of cellular toxicity. However, these effects required much higher concentrations of rhIL-10, and viral production was only partially suppressed. rhIL-10 also slightly inhibited HIV-induced cytopathicity in ATH-8, a tetanus toxoid-specific, retrovirally immortalized T-cell line, but had no effect on HIV replication in the H9 and MOLT-4 T cell lines. Thus, rhIL-10 appears to inhibit HIV replication predominantly in cells of the M/M lineage. This effect may serve to reduce viral production in patients with AIDS. However, additional studies will be needed to more precisely define its physiologic role in this disease.

CD4-Positive T-Lymphocytes↗
PubMed1994

Oncology and hematology.

Net overexpression or derangements of PTK-encoding oncogenes and ras serve as critical driving forces in the evolution of many epithelial and lymphohematopoietic cancers. The ability to impede signal transduction through ras-based pathways could provide a powerful molecular target for therapy and prevention of a broad spectrum of malignant neoplasms.

Hematology↗
PubMed1993

Administration of pentosan polysulfate to patients with human immunodeficiency virus-associated Kaposi's sarcoma.

BACKGROUND: Neovascularization induced by basic fibroblast growth factor (basic FGF) or FGF-like cytokines is thought to play a substantial role in the pathogenesis of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma. Pentosan polysulfate has been shown to inhibit basic FGF and FGF-like dependent tumor growth both in vitro and in vivo. Moreover, it has been found to inhibit the growth of Kaposi's sarcoma-derived spindle cells in vitro. These observations suggested that pentosan polysulfate might be worth exploring as a potential agent for the treatment of Kaposi's sarcoma. PURPOSE: The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose of pentosan polysulfate in patients with HIV-associated Kaposi's sarcoma and whether or not this compound had activity against this neoplasm. METHODS: Sixteen HIV-seropositive patients with Kaposi's sarcoma received pentosan polysulfate via continuous venous infusion for 3-6 weeks and then received a subcutaneous dose three times per week. Three different doses of pentosan polysulfate were administered: 2 mg/kg per day by infusion followed by 2 mg/kg per dose given subcutaneously (six patients), 3 mg/kg per day by infusion followed by 3 mg/kg per dose given subcutaneously (five patients), and 4 mg/kg per day by infusion followed by 4 mg/kg per dose given subcutaneously (five patients). Five of the 16 patients in the study also received injections of 1 mg of pentosan polysulfate into two different lesions two times a week for 3 weeks, followed by intralesional therapy once weekly. After receiving pentosan polysulfate for 6 weeks, patients were administered 100 mg zidovudine (AZT) orally every 4 hours in conjunction with pentosan polysulfate. RESULTS: The maximally tolerated dose of pentosan polysulfate given by continuous venous infusion was found to be 3 mg/kg per day. No patient had an objective clinical antitumor response to either systemic or intralesional pentosan polysulfate administration; however, three patients had stable Kaposi's sarcoma for 3-27 weeks. No statistically significant effect on CD4 cells or serum HIV p24 antigen was noted during pentosan polysulfate administration. Dose-limiting toxic effects were characterized by anticoagulation and thrombocytopenia and were reversible. CONCLUSION: Pentosan polysulfate was well tolerated in this patient population. However, no objective tumor response or evidence of anti-HIV activity was noted; therefore, no claim of activity can be made in this trial. IMPLICATION: Continued investigation into the use of angiogenesis inhibitors with improved activity and toxicity profiles or different mechanisms of action is warranted.

Adult↗
PubMed1993

Oncology.

Explore the source record for details and available documents.

Chromosome Mapping↗
PubMed1993

Trends in program project grant funding at the National Cancer Institute.

In summary, analysis of the P01 program indicates that differences exist in scores and funding requirements between purely basic and translational P01s; P01 funding has been stable and the P01 policies consistent; growth in average costs for P01s has lagged compared to R01s; P01 grantees have a higher success rate than R01 grantees; priority score compression reduces the P01 payline without reducing the number of grants funded; exception funding in P01s expands the number of grants awarded and helps to meet the scientific program needs of the NCI; almost all R01 and P01 applications in the first quartile are funded; comparably ranked R01s and P01s are funded at equivalent percentages of recommended funding levels; the percentage of approved funds awarded declines as scores for R01s and P01s become less favorable. Because the resources available are finite, the NCI carefully considers the competing demands for RPG funds. On balance, however, the P01 program is still in good health. In combination with the other methods we use to make RPG awards, the P01 program is a vital component of our research grant program. Faced with budget realities, however, some difficult decisions have to be made. The NCI is open to suggestions on how to distribute research funds to best promote cancer research throughout the country. The NCI is particularly interested in hearing researchers' perceptions of problems so that, whenever it is appropriate, we can modify our course. There are important questions to consider for the future. Should there be greater or lesser use of RFAs in allocating resources for P01 grants? What algorithm optimally distributes resources among R01s, P01s, and other funding instruments in the RPGs? Should exceptions be used more or less heavily in the P01 funding process? Should other grant programs outside the RPG budget, such as the P50 SPORE program, be used to relieve pressures on the P01 budget? Should the number of projects within P01s be limited? How can peer review groups be given opportunities to provide priority scores that better reflect distinguishable differences in highly meritorious P01s? Should P01 scores be normalized? How could the R01 percentile concept be applied to P01s? How can the results from standing study sections be synchronized with results from ad hoc review groups? What changes in peer review procedures would promote equitable score distributions and budget recommendations across years? How can the NCI provide stability for established P01s without impinging on the ability of new P01s to enter the system?(ABSTRACT TRUNCATED AT 400 WORDS)

Financing, Government↗
PubMed1993

Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study.

Human immunodeficiency virus type 1 (HIV-1) strains were isolated from nine patients before and after prolonged therapy with either an alternating regimen of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) (AZT/ddC) or 2',3'-dideoxyinosine (ddI) alone. All strains obtained from four patients who received AZT/ddC for up to 41 mo were highly insensitive to AZT in vitro. Only one strain obtained after AZT/ddC therapy showed reduced susceptibility to ddC in addition to AZT and had previously unreported amino acid substitutions in the viral polymerase-encoding pol region, whereas three other strains had one or more of the five previously reported AZT-related mutations. In five HIV-1 strains from patients who received ddI for up to 29 mo, no appreciable decrease in sensitivity to ddI was detected. Two strains isolated after ddI therapy had no significant amino acid mutations, although three strains had a mutation reportedly associated with ddI administration. These data suggest that HIV-1 develops reduced susceptibility to AZT more readily than to ddC and ddI and/or that the reduced susceptibility to ddC and ddI is modest in degree. Moreover, the present data suggest that an alternating regimen of AZT and ddC does not block the emergence of AZT-insensitive variants. It should be noted, however, that the current results do not provide a basis for concluding that AZT/ddC or ddI is inferior, equivalent, or superior to AZT as therapy of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

The challenge of cancer research.

The challenge of cancer research can be summarized by simple statistics. In 1992, more than 1.1 million Americans are expected to develop cancer, and roughly 520,000 are expected to die from cancer. The National Cancer Institute's (NCI's) mission is to eradicate the death and suffering from cancer, to cure cancer once it starts and ultimately to prevent cancer. To this end, initiatives that promote continued development of sophisticated molecular technologies and clinical application of those technologies to the prevention, diagnosis and treatment of cancer are of surpassingly high priority. Epidemiological studies tell us that at least 30-50% of cancer is directly related to smoking, diet and environmental factors. Treatment studies indicate that significant gains in survival are possible and have already been achieved in some cancers, with promise from new drugs and other modalities (including genetic engineering) for still other cancers. Prevention strategies such as smoking reduction, diet, environmental measures, chemoprevention and vaccine development have the potential to achieve a substantial reduction in cancer mortality. This reduction, realized over two decades, would result in at least 100,000 lives saved per year in this country, and a large number can be saved just by applying what we already know.

Female↗
PubMed1993

Challenges in the therapy of HIV infection.

Drugs that inhibit human immunodeficiency virus (HIV) replication have been shown to have clinical utility in patients with HIV infection. However, the immunological improvement induced by available anti-HIV therapies in patients with acquired immune deficiency syndrome (AIDS) is incomplete and transient. Explanations for this may include immunological barriers to complete reconstitution, low therapeutic indices of the available drugs, and the development of viral resistance. An understanding of these processes, as discussed here by Robert Yarchoan and colleagues, may provide important leads for the development of improved therapy for AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Challenges in the therapy of HIV infection.

Drugs that inhibit HIV replication have been shown to have clinical utility in patients with HIV infection. However, the immunological improvement induced by available anti-HIV therapies in patients with AIDS is incomplete and transient. Explanations for this may include immunological barriers to complete reconstitution, low therapeutic indices of the available drugs, and the development of viral resistance. An understanding of these processes may provide important leads for the development of improved therapy for AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Effect of a recombinant CD4-IgG on in vitro T helper cell function: data from a phase I/II study of patients with AIDS.

Ten patients with AIDS were enrolled in a phase I/II protocol of recombinant CD4-IgG (rCD4-IgG) treatment. Patients' peripheral blood leukocytes (PBL) were tested before, during, and after therapy with rCD4-IgG for T helper (TH) cell function assessed by antigen- and mitogen-stimulated proliferation and interleukin-2 production in response to influenza A virus, allogeneic PBL (alloantigens), and phytohemagglutinin. Although clinical benefit was not evident, rCD4-IgG treatment was associated with rapid and potent improved TH cell function for two of three stimuli tested in 90% of the patients. These data are complemented by an in vitro experimental model that demonstrates the opposing immunologic effects of rgp120 and rCD4-IgG on TH cell function of PBL from uninfected individuals. Thus, restoration of TH cell function by rCD4-IgG in the absence of increased CD4 cell counts could be due to removal of an immunosuppressive factor, possibly gp120. These findings suggest that rCD4-IgG can induce partial restoration of immune function in AIDS patients, even in the absence of apparent short-term clinical benefit.

Acquired Immunodeficiency Syndrome↗
PubMed1993

A pilot study of sequential therapy with zidovudine plus acyclovir, dideoxyinosine, and dideoxycytidine in patients with severe human immunodeficiency virus infection.

A pilot study was initiated to explore a sequential combination antiretroviral regimen in 21 patients with AIDS or advanced human immunodeficiency virus (HIV) infection, who had received little or no prior anti-HIV therapy. The mean entry CD4 cell count was 184/mm3. Patients received 3-week cycles consisting of zidovudine plus acyclovir, dideoxyinosine, and dideoxycytidine for 1 week each. Overall, the regimen was well tolerated for up to 3 years. The principal toxicities were anemia, nausea, and vomiting; 1 patient developed retinal lesions. The mean CD4 cell count reached a peak of 64 cells/mm3 above baseline at week 8 (P = .005 compared to baseline) and remained above baseline for > 40 weeks. Patients also gained weight and had decreases in serum HIV p24 antigen. Eight patients developed opportunistic infections or tumors. Only 4 patients died during 3 years of follow-up. This regimen appears to be generally tolerable and to have anti-HIV activity. Additional studies will be needed, however, to learn how to best combine the available agents in patients with HIV infection.

AIDS-Related Complex↗
PubMed1993

Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.

The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM. The mean drug concentration which yielded 50% p24 Gag negative cultures were substantially different: 0.06, 0.2, and 6 microM for AZT, ddC, and ddI, respectively. We found that AZT was preferentially phosphorylated to its triphosphate (TP) form in PHA-PBM rather than unstimulated, resting PBM (R-PBM), producing 10- to 17-fold higher ratios of AZTTP/dTTP in PHA-PBM than in R-PBM. The phosphorylation of ddC and ddI to their TP forms was, however, much less efficient in PHA-PBM, resulting in approximately 5-fold and approximately 15-fold lower ratios of ddCTP/dCTP and ddATP/dATP, respectively, in PHA-PBM than in R-PBM. The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase. We conclude that AZT, ddC, and ddI exert disproportionate antiviral effects depending on the activation state of the target cells, i.e., ddI and ddC exert antiviral activity more favorably in resting cells than in activated cells, while AZT preferentially protects activated cells against HIV infection. Considering that HIV-1 proviral DNA synthesis in resting lymphocytes is reportedly initiated at levels comparable with those of activated lymphocytes, the current data should have practical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy.

5'-Nucleotidase↗
PubMed1993

Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy.

PURPOSE: To investigate the occurrence of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy and factors associated with the development of these lymphomas. PATIENTS AND METHODS: The charts of 55 patients with advanced HIV infection receiving zidovudine (formerly known as azidothymidine [AZT])-based therapy and 61 patients receiving dideoxyinosine (ddI) were examined for the occurrence of NHL. Stored samples from the AZT-based treatment cohort were examined retrospectively for parameters predictive of the subsequent development of lymphoma. RESULTS: Eight of 55 patients receiving AZT-based therapy developed NHL, yielding an estimated probability of 12% (95% confidence interval [CI], 4.7% to 27.1%) after 24 months, and 29.2% (95% CI, 15.2% to 48.7%) after 36 months. Four of 61 patients receiving ddI developed NHL, yielding a 6.2% (95% CI, 2.1% to 17%) estimated probability after 24 months, and 9.5% (95% CI, 3.6% to 22.8%) after 36 months. The difference between these cohorts was not significant (two-tailed P [P2] = .13). Patients with less than 50 CD4 cells/microL developed NHL at a significantly higher rate (P2 = .0085). This was particularly true for patients who presented with primary CNS lymphoma (PCNSL). For patients receiving AZT-based therapy, pretreatment serum interleukin-6 (IL-6) levels were somewhat higher in those who subsequently developed NHL than in those who did not (P2 = .048). CONCLUSION: HIV-infected patients with profound immunodeficiency, especially those with less than 50 CD4 cells/microL, are at substantial risk of developing NHL and particularly PCNSL. Additional studies are needed to define the role of other factors such as IL-6 in the pathogenesis of these opportunistic tumors.

CD4-Positive T-Lymphocytes↗