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Biomedical subjects

P Goss

Publications and source records attributed to P Goss.

35 records · Page 2Linked to original sources
PubMed1995

A phase II trial of prednisone, oral etoposide, and novantrone (PEN) as initial treatment of non-Hodgkin's lymphoma in elderly patients.

This phase II study was designed to improve the outcome of elderly patients with advanced aggressive non-Hodgkin's lymphomas (NHL's) by employing a novel chemotherapy regimen PEN (prednisone, oral etoposide and mitoxantrone), as initial treatment. Between July 1991 and September 1993, 43 patients (14 male, 29 female) aged 66-82 years (median 74) received 1-8 (median 4) courses of PEN (total 192) q28 days (prednisone 50 mg od x 14 days, oral etoposide 50 mg od x 14 days and mitoxantrone 8 mg/m2 i.v. day 1) in the ambulatory setting. Pathologies of patients' tumors classified by the Working Formulation (WF) included C = 4, D = 2, E = 1, F = 7, G = 25, H = 4. Eighteen patients (42%) had stage IV, 15 (35%) stage III, 9 (21%) stage II and 1 (2%) stage I disease. Nineteen patients (44%) had B symptoms, 7 (16%) primarily extranodal disease and 15 (35%) bone marrow involvement. Patients with congestive heart failure, current anti-failure medication or pretreatment Muga left ventricular ejection fraction (LVEF) of < 45% (median pretreatment 60%) were excluded from PEN. After a median follow-up of 8.5 months (range 1-30), 14 of 33 evaluable patients (42%) have achieved CR of their disease for 8+ months (range 4-19) and 6 (18%) PR for 6+ months (range 5-10), giving an overall response rate of 61%. Ten (30%) patients did not respond to PEN and 10 were not evaluable for response. Response to PEN was not predicted by any pretreatment characteristic.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Branching N-linked oligosaccharides in breast cancer.

Tumor progression in rodent and human tumors is commonly associated with changes in glycoprotein glycosylation, in particular increased beta 1-6GlcNAc-branching, a regulatory step in expression of polylactosamine and extended-chain Lewis antigens. Loss of the branched oligosaccharides in murine tumor cells either due to somatic mutation, or treatment of the cells with the oligosaccharide processing inhibitor swainsonine, blocks tumor cells invasion in vitro and reduces solid tumor growth in vivo. Swainsonine and other inhibitors of N-linked oligosaccharide processing may be useful anti-cancer drugs, a premise which has begun to be tested in humans.

Animals↗
PubMed1994

Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer.

A total of 409 postmenopausal patients with advanced metastatic breast cancer were randomized to receive either formestane (Lentaron) 250 mg every 2 weeks by intramuscular injection, or tamoxifen 30 mg/day orally. Treatment continued until tumor progression. The groups were well matched for pretreatment characteristics including age, performance status, hormone receptor status (patients with known negative receptor status of their primary tumor were excluded), site and extent of metastases, disease-free interval, and previous primary and adjuvant therapy. Patients were assessed for antitumor efficacy at 3-monthly intervals using UICC criteria. Of the 348 patients evaluable for response, 33% had an objective response to formestane (14 complete and 43 partial responses), while 37% had an objective response to tamoxifen (10 complete and 54 partial responses). Median duration of response was 15 months for formestane and 20 months for tamoxifen; survival was 35 and 38 months respectively. There were no statistically significant differences between the treatments for all these variables, but time to disease progression and time to treatment failure significantly favoured tamoxifen. Systemic tolerability was excellent for both treatments. Local side effects due to intramuscular injection of formestane were mild and transient. In this comparative trial of first-line therapy for advanced breast cancer, formestane gave results comparable to tamoxifen for both efficacy and tolerability. We conclude that formestane is an effective and well tolerated addition to the therapeutic options available for the treatment of postmenopausal women with advanced breast cancer.

Adult↗
PubMed1994

Measuring swainsonine in serum of cancer patients: phase I clinical trial.

Swainsonine, an indolizidine alkaloid and competitive inhibitor of Golgi alpha-mannosidase II (EC 3.2.1.114), reduces tumor growth and stimulates immune function in mice. On the basis of these observations, a phase I clinical trial was initiated to determine whether swainsonine could be administered safely to cancer patients. We describe a method for extraction, acetylation, and quantification of swainsonine in human serum samples. Methyl alpha-D-mannopyranoside and methyl beta-D-galactopyranoside were added to serum samples as internal standards and, after sequential extraction of lipids and proteins with chloroform and acetonitrile, respectively, samples were acetylated with acetic anhydride and 4-dimethylaminopyridine and separated by gas-liquid chromatography. The identity of swainsonine and the internal standards after their extraction from serum and acetylation was confirmed by gas chromatography/mass spectrometry. Swainsonine was recovered at an efficiency of 90%, relative to internal standards, and calibration graphs were rectilinear from 3 to 18 mg/L with a detection limit of approximately 0.1 mg/L. The CV for multiple samples was < or = 6.7%. In patients receiving swainsonine (50-550 micrograms/kg per day) continuously for 5 days by intravenous infusion, serum concentrations of the drug reached 3-11.8 mg/L, 100 to 400 times greater than the 50% inhibitory concentration for Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. Accurate measurements of swainsonine in biological fluids with this method should facilitate further clinical studies with the drug.

Acetylation↗
PubMed1993

Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q.

Signal transduction through the T-cell receptor and cytokine receptors on the surface of T lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates. Because neither the T-cell receptor nor cytokine receptors contain intrinsic kinase domains, signal transduction is thought to occur via association of these receptors with intracellular protein tyrosine kinases. Although several members of the SRC and SYK families of tyrosine kinases have been implicated in signal transduction in lymphocytes, it seems likely that additional tyrosine kinases involved in signal transduction remain to be identified. To identify unique T-cell tyrosine kinases, we used polymerase chain reaction-based cloning with degenerate oligonucleotides directed at highly conserved motifs of tyrosine kinase domains. We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. The cDNA of EMT predicts an open reading frame of 1866 bp encoding a protein with a predicted size of 72 Kd, which is in keeping with its size on Western blotting. A single 6.2-kb EMT mRNA and 72-Kd protein were detected in T lymphocytes and NK-like cell lines, but were not detected in other cell lineages. EMT contains both SH2 and SH3 domains, as do many other intracellular kinases. EMT does not contain the N-terminal myristylation site or the negative regulatory tyrosine phosphorylation site in its carboxyterminus that are found in the SRC family of tyrosine kinases. EMT is related to the B-cell progenitor kinase (BPK), which has recently been implicated in X-linked hypogammaglobulinemia, to the TECI mammalian kinase, which has been implicated in liver neoplasia, to the more widely expressed TECII mammalian kinase, and to the Drosophila melanogaster Dsrc28 kinase. Sequence comparison suggests that EMT is likely the human homologue of a recently identified murine interleukin-2 (IL-2)-inducible T cell kinase (ITK). However, unlike ITK, EMT message and protein levels do not vary markedly on stimulation of human IL-2-responsive T cells with IL-2. Taken together, it seems that EMT is a member of a new family of intracellular kinases that includes BPK, TECI, and TECII. EMT was localized to chromosome 5q31-32, a region that contains the genes for several growth factors and receptors as well as early activation genes, particularly those involved in the hematopoietic system. Furthermore, the 5q31-32 region is implicated in the genesis of the 5q- syndrome associated with myelodysplasia and development of leukemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Three cases of congenital adrenal hypoplasia: a cause of salt-wasting and mortality in the neonatal period.

Three infants with congenital adrenal hypoplasia are described. The two surviving infants were detected and successfully treated in the neonatal period due to a suggestive family history (Case 1) and antenatal maternal oestriol screening (Case 2). The modes of inheritance, diverse clinical presentation, associated conditions, diagnostic work-up and pathology of congenital adrenal hypoplasia in these three infants is discussed.

Adrenal Glands↗
PubMed1989

Kaposi's sarcoma and AIDS: a variable spectrum.

A cohort of 61 patients with Kaposi's sarcoma (KS) and AIDS was seen in the Oncology Unit of the Toronto General Hospital between 1982 and 1986. In an attempt to identify prognostic variables, laboratory and clinical parameters were examined using Kaplan-Meier estimates and the Cox Regression Model. All patients were male, median age 36 years (range 23-52). In 49 patients KS was diagnosed before any AIDS-associated opportunistic infection (OI). Three patients had concurrent KS and OI, and nine patients developed KS one or more months after an OI. Only 11 patients had stage I or II disease, 34 stage III, and 15 stage IV. Only 18 patients (30%) were asymptomatic. Twenty-six percent had fever, night sweats, or weight loss, 11% had minor opportunistic infections, and 33% had both symptom complexes. The median overall survival was 10.5 months. The survival of patients who received chemotherapy for their KS was not significantly different from the survival of non-treated patients (p = 0.7). Although significant differences in survival could not be seen between stages, patients with both systemic symptoms and minor opportunistic infections had significantly shorter survival (p = 0.03). Survival from the onset of KS was significantly shorter for patients who had experienced a previous OI, but their overall survival from the date of diagnosis of AIDS was not significantly different from those patients presenting with KS alone. When analyzed separately the laboratory parameters of hemoglobin (p less than 0.0001), absolute lymphocyte count (p = 0.03), platelet count (p = 0.04), and T4 level (p = 0.05) demonstrated a significant relationship with survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1986

Aromatase inhibitors and the treatment of breast cancer.

Inhibition of aromatase to reduce estrogen production by peripheral and ovarian tissue could be a useful approach to treating hormone-dependent breast cancer. Several C19, 17 keto steroids have been identified as aromatase inhibitors. The most potent of these cause rapid competitive inhibition followed by enzyme inactivation. Injections of the compounds caused inhibition of peripheral aromatization in monkeys. In rats, these treatments result in inhibition of ovarian aromatase and estrogen secretion, accompanied by marked regression of carcinogen(DMBA or NMU)-induced mammary tumors. To date, 60 postmenopausal patients with advanced metastatic breast cancer and unselected for the presence of estrogen receptors have been treated with once weekly injections of 4-OHA. The mean estradiol level measured in 14 patients was significantly reduced to 36% of pretreatment values after 1 month and remained at this level for up to 4 months. There was no effect of treatment on gonadotropin levels. Although all patients had relapsed from previous therapy, complete or partial tumor regression occurred in 30% of patients while 15% had static disease. The results indicate that in these patients the responses are due to inhibition of peripheral aromatization and that 4-OHA may be of value in treating postmenopausal breast cancer.

Adult↗
PubMed1986

Aromatase inhibitors and their potential clinical significance.

Estrogen biosynthesis occurs not only in reproductive tissues of the female but also in such diverse sites as testes, adipose and muscle. Our rationale for the clinical use of aromatase inhibitors is that compounds interacting with aromatase in all tissues could provide both selective and effective inhibition of estrogen production. The most potent inhibitor identified by us to date is 4-hydroxyandrostene-3,17-dione (4-OHA). This compound causes rapid competitive inhibition followed by irreversible inactivation of aromatase. Treatment of rats with 4-OHA results in inhibition of ovarian aromatase and estrogen secretion, accompanied by marked regression of carcinogen induced mammary tumors. Using rhesus monkeys, marked inhibition of peripheral aromatization by 4-OHA was also demonstrated. The first clinical study with a selective aromatase inhibitor was recently carried out using once weekly injections of 500 mg 4-OHA in 60 postmenopausal patients with advanced metastatic breast cancer and unselected for the presence of estrogen receptors. The mean serum estradiol level reduced to 36% of pretreatment values for at least 4 months. No effect of treatment on gonadotropin levels occurred indicating that the reduction in estrogen levels was due to inhibition of peripheral aromatization. In spite of the fact that all patients had relapsed from previous therapy, complete or partial tumor regression occurred in 30% of patients while 15% had static disease. Although the optimum dose of 4-OHA has not yet been established, this aromatase inhibitor appears to be of value in treating postmenopausal breast cancer and may be beneficial in other diseases associated with estrogens.

Androstenedione↗
PubMed1984

4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer.

4-hydroxyandrostenedione, a potent inhibitor of the aromatase (oestrogen synthetase) system, was given to 11 patients with metastatic breast cancer. After a single 500 mg intramuscular injection a sustained reduction of serum oestradiol was observed for at least 1 week in all patients in whom the steroid was measured. 4 patients responded to treatment for periods of up to 4 months, and healing of bone metastases and reduction in size of soft-tissue metastases was evident. The only side-effects were pain at the injection site and hot flushes. 4-hydroxyandrostenedione is a new and specific aromatase inhibitor which shows promise in the treatment of patients with metastatic breast cancer.

Adult↗
PubMed1978

Chromosome damage and DNA repair induced in human fibroblasts by UV and cholesterol oxide.

In human fibroblasts, cholesterol oxide induced a similar degree of chromosome damage (8.6% of metaphases) and DNA repair synthesis (8-10% of cells with lightly-labelled nuclei) as low doses of ultraviolet light (UV), but did not produce single-strand DNA breaks or DNA damage detectable by inhibition of thymidine incorporation. Chromosome aberrations were detected up to 8 weeks after treatment with cholesterol oxide and UV. Combined treatments had almost additive effects on the frequency of chromosome aberrations but not on repair synthesis. Multiple daily doses of UV did not cause more aberrations than a single dose. Attempts to transform two fibroblast strains from normal donors and three derived from melanoma patients using single and combined treatments of UV, cholesterol oxide and hyperthermia (40 degrees) were unsuccessful.

Adolescent↗
PubMed1977

The effect of hyperthermia and melphalan on survival of human fibroblast strains and melanoma cell lines.

The survival of four human fibroblast strains and seven malignant melanoma cell lines was determined by the colony formation method following 4-hr treatment with various concentrations of melphalan, with or without simultaneous exposure to hyperthermia (42 degrees). The two amelanotic melanoma lines (MM127 and MM253) were 10 times more sensitive to melphalan at 36 degrees than were the four fibroblast strains, the five pigmented melanoma lines being of intermediate sensitivity. Sensitivity to melphalan was usually accompanied by sensitivity to heat, while combined treatment was not only synergistic in most lines but increased the differential between fibroblasts and melanoma cells. Survival studies carried out at 36 degrees, 40 degrees, 42 degrees, and 44 degrees, using human fetal lung fibroblasts and MM253 cells, showed that 42 degrees gave the greatest differential effect and allowed reasonable survival of the normal cells. Time-survival comparison of the same two lines demonstrated that there was no advantage in prolonging hyperthermia unless melphalan was used. A more convenient method for determination of survival was developed based on thymidine uptake of colonies grown in Linbro wells.

Cell Line↗
PubMed1976

Temperature-sensitive DNA repair of ultraviolet damage in human cell lines.

Following exposure to ultraviolet irradiation (UV), two of three human fibroblast strains and one of three melanoma cell lines showed lower rates of thymine dimer excision during 24 h at 40 degrees C than at 36 degrees C. All lines had lower rates at 32 degrees C. Autoradiographic studies of three fibroblast strains and four melanoma lines incubated for four hours after irradiation revealed decreased unscheduled DNA synthesis at 42 degrees C compared with 36 degrees C. The rate of semiconservative DNA synthesis was decreased at the upper temperature in both series of experiments. All eight cell lines tested showed decreased repair at 42 degrees C, as judged by slower sedimentation and increased heterogeneity of parental DNA in alkaline sucrose gradients. Experiments using the DNA synthesis inhibitor Actinomycin D suggested that these effects were due to temperature-sensitive repair synthesis. In the two lines studied, preincubation of cells at 42 degrees C apparently increased the extent of UV damage. Although by no means conclusive, these results are consistent with the possibility that temperature-sensitive DNA repair is a contributory factor in some cases of solar carcinogenesis.

Autoradiography↗