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P S Gill

Publications and source records attributed to P S Gill.

At least 19 recordsLinked to original sources
PubMed1999

Antineoplastic urinary protein inhibits Kaposi's sarcoma and angiogenesis in vitro and in vivo.

Kaposi's sarcoma (KS) is the most common tumor in human immunodeficiency virus infection and acquired immune deficiency syndrome. Recent clinical trials with human chorionic gonadotropin (hCG) prepared from early pregnancy urine have shown encouraging results in the resolution of KS lesions. A urinary protein with antitumor activity, ANUP (antineoplastic urinary protein), a dimer of 32 kD, has previously been shown to inhibit the growth of various tumor cell lines in vivo. It was thus studied for its activity in KS cell lines in vitro and in vivo to determine whether it could be a source of the anti-KS activity observed in hCG preparations. ANUP is a strong growth inhibitor for KS cell lines, but has little or no effect on fibroblast, aortic smooth muscle, T- and B-lymphocyte, and monocyte cell lines. ANUP also inhibited the proliferation of endothelial cell lines, suggesting that the in vitro effects were endothelial cell lineage-specific. However, ANUP antibodies did not block the inhibitory effect of certain commercial preparations of hCG, previously shown to be active in KS. Thus, the active protein in these commercial preparations of hCG may be distinct from ANUP. The antitumor activity of ANUP was further confirmed in a chicken allantoic membrane (CAM) assay in which vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF)-induced angiogenesis was inhibited by ANUP in a dose-dependent manner. In vivo activity of ANUP was demonstrated in the murine model of KS, where ANUP inhibited tumor growth. ANUP is thus a potential candidate for development in the treatment of KS and other diseases in which angiogenesis plays an important role.

Adult↗
PubMed1999

Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells.

Angiogenesis is a critical step in a benign tumor's evolution toward malignancy and metastasis. Tumor cells acquire such a phenotype by their ability to secrete angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF receptors (VEGFRs) flt-1/VEGFR-1 and Flk-1/ KDR/VEGFR-2 are restricted to activated endothelial cells, with the highest expression being in the tumor vasculature. The present study was undertaken to target the VEGFRs. Targeted toxins were developed by recombinant methods by fusing VEGF165 or VEGF121 to the diphtheria toxin (DT) translocation and enzymatic domain (DT390-VEGF165 or DT390-VEGF121). Both fusion proteins were found to be highly toxic to proliferating endothelial cells but not to vascular smooth muscle cells. The fusion protein is also active in Kaposi's sarcoma, a tumor type that expresses high levels of VEGFRs. These fusion proteins completely inhibit the basic fibroblast growth factor-induced growth of new blood vessels in the chick chorioallantoic membrane assay. Furthermore, the fusion toxin substantially retards the growth of Kaposi's sarcoma tumors in mice. Because nearly all tumors induce local angiogenesis with high VEGFR expression, VEGF-derived toxins may have wide application in cancer therapy.

Animals↗
PubMed1998

Evidence for multiclonality in multicentric Kaposi's sarcoma.

Kaposi's sarcoma (KS) develops in a variety of clinical states and is the most common tumor seen in patients with HIV-1 infection. KS develops as a multifocal mucocutaneous disease with subsequent spread to visceral organs, and it has been argued to be a benign proliferation caused by its multifocality at initial presentation, lack of aneuploidy, and spontaneous regression upon withdrawal of immunosuppressive agents in iatrogenically induced disease. We wished to determine whether KS lesions are clonal, indicative of a true neoplasm. Also, we tested whether multifocal KS lesions are clonally related, derived from a common progenitor cell or of independent cellular origin. We studied the X-chromosome inactivation pattern of the human androgen receptor gene in tumor biopsies of women with KS. This procedure tests for the clonality of a tissue specimen, a hallmark of neoplasia. Each specimen was microdissected to minimize normal cell contamination. Of 12 evaluable cases, 10 were HIV-seropositive and 2 were HIV-seronegative. Twenty-four biopsies from the 12 patients were examined. Five cases were consistent with individual KS lesions being clonal. In two cases, multiple KS specimens derived from the individual patients had different androgen receptor alleles inactivated, proving unequivocally that these KS lesions arose independently from distinct transformed cells. In seven cases, only a polyclonal pattern of inactivation was observed, whereas two others had tumor areas of both clonal and polyclonal inactivation patterns. These findings suggest that KS can be a clonal neoplasm, and in some of the cases multiple KS lesions in a given patient can arise from independent cellular origins and acquire clonal characteristics. The polyclonal inactivation pattern observed in other KS lesions may represent a premalignant stage or false negative results.

Adult↗
PubMed1998

Detection and titration of human herpesvirus-8-specific antibodies in sera from blood donors, acquired immunodeficiency syndrome patients, and Kaposi's sarcoma patients using a whole virus enzyme-linked immunosorbent assay.

A human herpesvirus-8 (HHV-8) enzyme-linked immunosorbent assay (ELISA) with a whole virus lysate as antigen was developed and used to measure the seroprevalence rate and levels of IgG antibodies to HHV-8 in sera/plasma of various patient groups and blood donors. The virus antigen was prepared from the KS-1 cell line, which produces lytic virus, and therefore contains a broad array of viral proteins. Seroprevalence studies using this ELISA showed the following: 10 of 91 blood donors (11%) had an average HHV-8 antibody titer of 118; 67 of 72 (93%) classic Kaposi's sarcoma (KS) patients were positive with an average titer of 14,111; and 57 of 62 (92%) KS/human immunodeficiency virus (HIV) patients were positive with an average titer of 4,000. A study on a very limited number of serial serum samples from patients before and after diagnosis with KS showed highly elevated antibody titers to HHV-8 virus after KS lesions developed. Preliminary data show that 50% of the sera from HIV-1(+) homosexual patients contain IgG antibodies to HHV-8 suggesting that this population is at high risk for developing KS. Antibody results correlated well with the confirmatory immunofluorescent assays (IFA) using KS-1 cells as the substrate. This HHV-8 IgG antibody detection ELISA is sensitive and specific and does not cross-react with Epstein-Barr virus (EBV) or other human herpesviruses. The results of this HHV-8 antibody survey suggest that this rapid ELISA assay can be used to screen large numbers of sera to find those at risk for developing KS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Interleukin-1 regulation of corticotropin-releasing factor (CRF), glucocorticoid receptor, c-fos and c-jun messenger RNA in the NPLC-KC cell line.

The NPLC-KC human hepatoma cell line expresses corticotropin-releasing factor (CRF) and it has been demonstrated that CRF secretion and synthesis in this cell line increases in response to activators of the protein kinase A (PKA) and C (PKC) pathways as well as interleukin-1 (IL1). CRF expression with all three agents can be inhibited with the synthetic steroid-dexamethasone (DEX). In this report, we have examined the effect of IL1 (beta form) in the presence and absence of DEX on CRF mRNA (mRNA) expression as well as the expression of human glucocorticoid receptor (GR) mRNA and the mRNA of the proto-oncogenes (c-jun and c-fos) that have been implicated in CRF regulation. NPLC-KC cells were incubated with picomolar concentrations of IL1. Following this total RNA was extracted from the cells and Northern Blots were probed with 32P-labelled human DNA probes for the CRF, GR, c-jun and c-fos genes. Levels of mRNA expression were measured using a PhosphoImager and were normalized to mRNA levels of control probe glyceraldehyde-3-phosphate dehydrogenase (GAPD). CRF mRNA was significantly increased with IL1 treatment in a time and concentration dependent manner. CRF mRNA expression increased with increasing concentrations of IL1 over the range of 1-100 pM; expression of CRF mRNA also peaked after 24 h of 100 pM IL1 treatment and reached a level of expression approximately seven times higher than control. This pattern of expression was significantly inhibited in the presence of 100 nM DEX. Levels of the GR, c-fos and c-jun mRNAs were also significantly increased in the presence of IL1 and inhibited when DEX was co-incubated with IL1. The results reveal that IL1 stimulation of CRF mRNA expression by IL1 in the NPLC-KC cell line is accompanied by activation of GR mRNA as well as the mRNA of the immediate early genes--c-fos and c-jun. The results also demonstrate that this cell line may serve as a model system for the molecular mechanisms by which IL1 regulates CRF in central nervous system (CNS) neurons.

Carcinoma, Hepatocellular↗
PubMed1998

Emerging treatments for epidemic (AIDS-related) Kaposi's sarcoma.

Kaposi's sarcoma (KS) is an opportunistic tumor that develops with increased frequency (100,000-fold) after HIV infection. KS causes significant morbidity from mucocutaneous involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evaluated in patients with limited tumor burden. These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the dipeptide IM 862, TNP-470, Col-3, and thalidomide; 2) topical and systemic retinoids; 3) antiviral agents specific for Kaposi's sarcoma herpesvirus and human herpesvirus-8, or HIV; and 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneous disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal anthracyclines and paclitaxel, with and without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies.

AIDS-Related Opportunistic Infections↗
PubMed1998

Phase II trial of liposomal daunorubicin in the treatment of AIDS-related pulmonary Kaposi's sarcoma.

PURPOSE: Kaposi's sarcoma (KS) is the most common tumor in patients with AIDS and can be fatal in patients with lung involvement. Systemic chemotherapy is the most effective treatment for pulmonary KS. We thus conducted this study to determine the efficacy of liposomal daunorubicin in the treatment of patients with pulmonary KS. METHODS: Patients with biopsy-proven, symptomatic pulmonary KS were accrued. Liposomal daunorubicin was given at a dose of 60 mg/m2 intravenously every 2 weeks. Response was monitored by chest radiographs, pulmonary function tests, arterial blood gases, and grading of pulmonary symptoms. RESULTS: Fifty-three male patients were accrued. The median CD4+ lymphocyte count was 13/microL (range, 0 to 200); 70% reported a prior AIDS-defining opportunistic infection. All patients were symptomatic, with cough reported in all patients, shortness of breath in 94%, and hemoptysis in 55%. The mean study entry diffusing capacity of carbon monoxide (DLCO) was 58.5% (percent of predicted). The median dose of liposomal daunorubicin delivered was 360 mg/m2 (range, 60 to 1,380). More than 75% of patients had complete or partial resolution of baseline pulmonary symptoms. Complete or partial improvement in DLCO was observed in 22%; complete or partial resolution of radiographic abnormalities was reported in 32%. The most common treatment-related toxicity was neutropenia, which occurred in 85%. There were no instances of cardiac toxicity observed, even at high cumulative doses. CONCLUSION: Liposomal daunorubicin at 60 mg/m2 is safe and active in patients with pulmonary KS. Trials combining liposomal daunorubicin with other active agents in KS should be considered.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

AIDS-Related Opportunistic Infections↗
PubMed1997

Effect of doctors' ethnicity and country of qualification on prescribing patterns in single handed general practices: linkage of information collected by questionnaire and from routine data.

OBJECTIVES: To test whether Asian general practitioners who qualified in the Indian subcontinent prescribe items more often, more expensive items, and fewer generic drugs than their British trained Asian and non-Asian counterparts. DESIGN: Linkage study using data collected by questionnaire and from routine sources. SETTING: General practices in England. SUBJECTS: 155 single handed general practitioners: 42 Asian doctors qualified in United Kingdom (group 1), 58 white doctors qualified in United Kingdom (group 2), and 55 Asian doctors qualified in Indian subcontinent (group 3). MAIN OUTCOME MEASURES: Prescribing cost (cost per ASTRO-PU), prescribing frequency (number of items per ASTRO-PU), and generic prescribing (percentage of drugs prescribed that are generic). RESULTS: Doctors in group 1 were significantly younger than those in the other groups and had a higher proportion of patients who were from deprived wards. There was no difference between the groups in the proportion of female doctors and total list size. After adjustment for confounding factors, there were no significant differences between the three groups for prescribing cost (16.58 (95% confidence interval 6.39 to 26.77) for group 1, 17.31 (6.92 to 27.69) for group 2, 17.80 (7.22 to 28.38) for group 3, P = 0.55); prescribing frequency (6.58 (4.60 to 8.40), 6.45 (4.70 to 8.30), 7.89 (6.16 to 9.64), P = 0.34); and generic prescribing (44.44 (38.95 to 49.93), 47.41 (42.12 to 52.70), 44.04 (38.75 to 49.33), P = 0.37). CONCLUSIONS: Asian doctors qualified from the Indian subcontinent did not differ from British trained doctors in their prescribing practice. This study refutes the common belief that Asian doctors are high volume and high cost prescribers.

Accreditation↗
PubMed1997

Phase I study of human chorionic gonadotropin given subcutaneously to patients with acquired immunodeficiency syndrome-related mucocutaneous Kaposi's sarcoma.

BACKGROUND: In vitro and in vivo clinical studies have shown that certain preparations of human chorionic gonadotropin have antitumor activity against Kaposi's sarcoma, the most common tumor in patients infected with human immunodeficiency virus type 1 (HIV-1). METHODS: A phase I trial was conducted in 18 male patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma. Successive cohorts of six patients each received human chorionic gonadotropin (A.P.L.; Wyeth-Ayerst, Radnor, PA) subcutaneously at doses of 5000 IU daily (level I), 10,000 IU three times a week (level II), or 10,000 IU daily (level III). Toxic effects, changes in reproductive hormone levels, HIV-1 RNA plasma levels, and response to therapy were evaluated. RESULTS: A.P.L. treatment was well tolerated at all dose levels, and no maximum-tolerated, dose-defined toxic effects were observed at the highest dose tested. The most common side effects were weight gain, increased libido, and increased energy. A persistent increase in testosterone level and a persistent decline in luteinizing hormone and follicle-stimulating hormone levels were seen over time. Major responses were observed in six patients. Partial remissions (> or =50% decrease in lesion numbers, volume, or surface area) were observed at dose level I and dose level II (two patients each); biopsy-confirmed complete remissions (resolution of all lesions) were observed at dose level III (two patients). All but one major response have persisted from 207 to more than 515 days. Nine patients had stable disease lasting 10 weeks or longer. CONCLUSIONS: A.P.L. given at daily doses ranging from 5000 to 10,000 IU has antitumor activity in patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma. A.P.L. can be given for more than 1 year with minimal side effects. Larger efficacy studies are warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma.

Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection and develops in nearly 30% of cases. The principal features of this tumor are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. KS-derived spindle cells induce vascular lesions and display enhanced vascular permeability when inoculated subcutaneously in the nude mouse. This finding suggests that angiogenesis and capillary permeability play a central role in the development and progression of KS. In this study, we show that AIDS-KS cell lines express higher levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VGF) than either human umbilical vein endothelial cells or human aortic smooth muscle cells. AIDS-KS cells and primary tumor tissues also expressed high levels of Flt-1 and KDR, the receptors for VEGF, while the normal skin of the same patients did not show any expression. We further demonstrate that VEGF antisense oligonucleotides AS-1 and AS-3 specifically block VEGF mRNA and protein production and inhibit KS cell growth in a dose-dependent manner. Furthermore, growth of KS cells in nude mice was specifically inhibited by VEGF antisense oligonucleotides. These results show that VEGF is an autocrine growth factor for AIDS-KS cells. To our knowledge, this is the first report that shows that VEGF acts as a growth stimulator in a human tumor. Inhibitors of VEGF or its cognate receptors may thus be candidates for therapeutic intervention.

AIDS-Related Opportunistic Infections↗
PubMed1997

IL-4R expression in AIDS-KS cells and response to rhIL-4 and IL-4 toxin (DAB389-IL-4).

Interleukin-4 (IL-4) is a pleiotropic cytokine affecting growth and differentiation of various cell types as well as regulating other cytokines. To study the effect of IL-4 on AIDS-related Kaposi's sarcoma (AIDS-KS) cells, we first examined the tumor cells for IL-4 receptor (IL-4R) expression. KS cells express a single 4 kB IL-4R-specific mRNA and 1828 +/- 408 high affinity IL-4 binding sites per cell with a dissociation constant (Kd) of 154 +/- 37 pM. Addition of recombinant human IL-4 (rIL-4) minimally inhibited AIDS-KS cell growth and expression of IL-6. We then studied the effects of a chimeric fusion toxin DAB389-IL-4 which exerts cellular toxicity only on cells expressing IL-4R. DAB389-IL-4 inhibited protein synthesis in AIDS-KS cells at low concentrations (IC50 of 5 x 10(-11) M). This effect was abrogated by neutralizing antibody to IL-4 (25D2). We conclude that KS cells express a functional IL-4R and this receptor could serve as a target for novel therapy with agents such as DAB389-IL-4.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Interleukin-4 in the treatment of AIDS-related Kaposi's sarcoma.

PURPOSE: To define the safety and toxicity of interleukin-4 (IL-4) when administered subcutaneously in patients with AIDS-related Kaposi's sarcoma (AIDS-KS); to evaluate the effect of IL-4 on immunologic and virologic parameters; and to preliminarily assess the response rate of IL-4 in AIDS-KS. PATIENTS AND METHODS: Eighteen patients with mucocutaneous, non-visceral AIDS-KS were treated with IL-4 at a dose of 1 mcg/kg subcutaneously, daily until unacceptable toxicity or for a maximum period of six months. Twelve (66%) patients had extensive mucocutaneous disease with over 25 lesions. Ten patients had received prior systemic chemotherapy. Seventeen had CD4+ lymphocyte counts less than 200/mm3. RESULTS: The most common adverse effects included headache in 78%, fever in 56%, chills in 44%, and edema in 44%. Hematologic toxicities consisted of grade 4 neutropenia (less than 500/mm3) in 33%, mild anemia in 22%. Transient elevation of liver enzymes was noted in 17%. A transient elevation in CD4+ lymphocyte counts occurred during the first two weeks of therapy. Four of eleven patients tested showed marked decline in plasma HIV RNA after four weeks. Partial remission was observed in one patient, lasting six months. Three other patients (17%) had stable disease: 7 weeks in one patient, and 10 weeks in each of the two other patients. CONCLUSION: Grade 4 neutropenia (absolute neutrophil count < 500/mm3) was the most common hematologic adverse effect with IL-4 in patients with AIDS-KS. In contrast to in vitro findings, there was a decrease in plasma HIV RNA after four weeks of IL-4 therapy in the majority of patients tested. IL-4 produced minimal anti-tumor effects in AIDS-KS with one partial remission in a patient with CD4 lymphocyte counts over 200/mm3. Further studies of IL-4 in AIDS-KS may be considered in patients with better immune status.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Mycosis fungoides and Sezary syndrome are not associated with HTLV-I infection: an international study.

Association between mycosis fungoides (MF), its leukaemic variant Sezary syndrome (SS) and the human T-cell lymphotropic virus type-I (HTLV-I) has been controversial, with the reported incidence of infection varying between 0% and nearly 100%. We studied 127 patients (85 MF, 28 SS, five Sezary cell leukaemia, four lymphomatoid papulosis, and five unspecified cutaneous T-cell lymphomas (CTCL)) originating from Europe (France, Spain, U.K., Portugal) or from U.S.A. (California) for the presence of HTLV-I infection markers. HTLV-I and -II serology were performed on 78 patients using standard immunological methods. Reverse transcriptase (RT) assay was also performed in 26 cases using an RT-PCR-based method of high sensitivity. Molecular analyses were performed on 215 DNA samples (121 from fresh PBMCs, 26 from PBMCs after short-term culture and 68 from skin lesions) by PCR amplification using HTLV-I and -II gag, pol, env, pX and LTR specific primers. Immunological tests were negative except for two sera which were indeterminate. PCR with all HTLV-I and -II primer pairs showed negative results in all 215 samples investigated. No RT activity was detected in short-term PBMC cultures of any of the 26 cases studied. The results of this large study from five different countries clearly indicate that MF and SS are not associated with HTLV-I infection.

Blotting, Western↗