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14 recordsLinked to original sources
PubMed1991

A phase II study alternating alpha-2a-interferon and gamma-interferon therapy in patients with chronic myelogenous leukemia.

Patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) were treated with a combination of alpha-interferon and gamma-interferon. Recombinant alpha-2a-interferon (Roferon-A, Hoffmann-LaRoche, Inc., Nutley, NJ) and recombinant gamma-interferon (Genentech, Inc., South San Francisco, CA) were administered on alternating weeks each at doses ranging from 2 to 10 MU/m2 given intramuscularly. Of the 27 patients, 11 (41%) achieved complete hematologic remission (CHR) and 3 (11%) achieved partial hematologic remission (PHR). Responses were seen among 9 of 22 (41%) patients treated during the chronic phase of the disease and in 2 of 5 (40%) patients treated during the accelerated phase/second chronic phase. Cytogenetic responses were seen in six patients, including one complete response and five minor responses. Toxicities included flu-like symptoms, which appeared to be more severe with gamma-interferon than with alpha-interferon, hypertriglyceridemia, and thrombocytopenia. In this limited study, an improved outcome was not observed for the combination regimen compared with alpha-interferon alone.

Adolescent↗
PubMed1989

Influence of matrix on concentrations of somatotropin measured in serum with commercial immunoradiometric assays.

Using immunoradiometric assays (IRMAs) from Hybritech Inc. (H) and Nichols Institute Diagnostics (ND), we measured somatotropin (human growth hormone, hGH) in serum samples obtained every 20 min for 24 h from 10 prepubertal subjects with short stature. Results obtained with the ND reagents were 2.74 times greater than those obtained with the H reagents (P = 0.00001, r = 0.94, SEE = 3.9, n = 720). We therefore compared the IRMAs with the standard hGH RIA from the National Institutes of Health (NIH) National Hormone and Pituitary Program, using the genetically engineered hGH preparations (from Genentech Inc.) 22-kDa hGH and methionated 20-kDa hGH. We also assayed human pituitary hGH (NIH, lot no. AFP-4793B). Each hGH preparation was diluted in three diluent buffer systems: horse serum from H and from ND, and human serum. The RIA and H-IRMA gave superimposable standard curves for all hGH preparations in each diluent. The methionated 20-kDa hGH was not detected in the H-assay. Use of human serum matrix in the ND-IRMA shifted the standard curve as compared with the horse-serum matrix, giving equivalent binding at lower concentrations; i.e., serum hGH was overestimated in samples assayed against standards diluted in horse serum. Quality-control materials (Ciba-Corning) yielded disparate results in all three assays, yet human serum pools containing hGH gave similar results in the H and the NIH assays, and higher values in ND. When a human serum standard was used in the ND assay, both IRMAs gave similar results to the RIA assay for human serum samples. Reference intervals for hGH should be determined by each analytical laboratory, to prevent misdiagnosis of patients. Furthermore, quality-control material should be of human origin, because commercially supplied quality-control material does not react the same as human serum in some hGH assays.

Child↗
PubMed1991

A collaborative study to establish a U.S. reference for tissue plasminogen activator (t-PA).

In 1987 the Second International Standard for tissue plasminogen activator (t-PA) was established by the World Health Organization following an international collaborative study. At that time, the Center for Biologics Evaluation and Research (CBER) decided to establish a national reference t-PA to be used in lot release potency testing of Alteplase, a licensed t-PA biological or of other t-PAs in development. A candidate recombinant t-PA (rt-PA) preparation was donated by Genentech, Inc. (South San Francisco, California) for this purpose and a collaborative study was launched to calibrate this material against the 2nd I.S. Four laboratories (including the Center for Biologics Evaluation and Research (CBER) and three manufacturers) participated in the study to establish the potency of the rt-PA preparation using a clot lysis assay. The results indicate that the potency of the U.S. reference for t-PA is 2900 international units (IU) per vial.

Humans↗
PubMed1983

Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity.

Human blood mononuclear leukocytes stimulated with toxoplasma antigen, concanavalin A, mezerein plus lentil lectin, or staphylococcal enterotoxin A secreted a factor (macrophage-activating factor, or MAF) that enhanced the capacity of human macrophages to release H2O2 and to kill toxoplasmas. The same lymphoid supernatants contained IFN gamma but not IFN alpha or IFN beta. The MAF activity of six of seven unfractionated supernatants was completely eliminated by a monoclonal antibody that neutralizes IFN gamma, and MAF in the remaining supernatant was almost completely neutralized. Native IFN gamma partially purified by two independent protocols to specific activities of 1 X 10(6) and 10(7) U/mg protein was enriched in MAF activity at least as much as in antiviral activity. The capacity of macrophages to secrete H2O2 after incubation in partially purified native IFN gamma (mean peak stimulation, 8.8-fold) was greater than with unpurified lymphokines (3.8-fold) and sometimes equaled or exceeded the capacity of freshly harvested monocytes. The MAF activity of the partially purified native IFN gamma preparations was abolished by monoclonal anti-IFN gamma. Finally, IFN gamma of greater than 99% estimated purity was isolated (at Genentech, Inc.) from bacteria transformed with the cloned human gene for this lymphokine. Recombinant IFN gamma had potent MAF activity, stimulating the peroxide-releasing capacity of macrophages an average of 19.8-fold at peak response and enhancing their ability to kill toxoplasmas from 2.6 +/- 1.3% for untreated cells to 54 +/- 0.4% for treated cells. Attainment of 50% of the maximal elevation in peroxide-releasing capacity required a geometric mean concentration of 0.1 antiviral U/ml of recombinant IFN gamma, which is estimated to be approximately 6 picomolar for this preparation. Peroxide secretory capacity and toxoplasmacidal activity of macrophages peaked 2-4 d after exposure to IFN gamma. Peroxide-secretory capacity remained elevated during at least 6 d of continuous exposure, but the effect of IFN gamma was reversed within about 3 d of its removal. Activation was usually but not invariably accompanied by characteristic changes in cell morphology. Thus, IFN gamma activates human macrophage oxidative metabolism and antimicrobial activity, and appeared to be the only factor consistently capable of doing so in the diverse LK preparations tested.

Adult↗
PubMed1985

Primate mammary development. Effects of hypophysectomy, prolactin inhibition, and growth hormone administration.

The pituitary gland has been found to be an important factor in mammary development in primates. Hypophysectomy in 12 sexually immature monkeys caused significant inhibition of estradiol (E2)-induced mammary growth and development. A histological index of mammary development in sexually immature hypophysectomized animals was lower (0.82) than in intact E2-treated controls (3.4; P less than 0.008). Hypophysectomy also inhibited growth of the mammary gland as judged by a size index. Despite the hypophysectomy, E2 stimulated some, albeit blunted, mammary growth and development, which may have been due to incomplete hypophysectomy. Selective inhibition of prolactin by ergot drugs in intact animals did not prevent full mammary development, suggesting that there may be pituitary mammogens other than prolactin, or that very low or unmeasurable concentrations of prolactin were sufficient to synergize with E2 to cause full acinar development. The mean histological index was 3.08 in E2-treated animals and 3.16 in animals treated with E2 plus pergolide. There was also no difference in the size of the glands. We evaluated the effect of growth hormone on mammary development by treating three hypophysectomized animals with pure 22,000 mol wt human growth hormone (hGH) (Genentech, Inc., South San Francisco, CA). We found that physiological or slightly supraphysiological concentrations of hGH in animals with unmeasurable prolactin were incapable of restoring the capacity of E2 to induce full mammary growth. These findings suggest that, if growth hormone is a mammary mitogen, that physiological concentrations are insufficient to synergize with E2 to induce full mammary growth or that other forms of hGH are mammogenic. Our studies suggest that the role of the pituitary gland in mammary mitogenesis in primates is more complicated than previously thought. They also raise the possibility that heretofore unidentified pituitary substances may be mammogenic.

Animals↗
PubMed1992

Clinical experience with tissue plasminogen activator stored at -20 degrees C.

We developed a new dilution technique that allows tissue plasminogen activator (t-PA) to be stored at -20 degrees C, as opposed to the -70 degrees C recommended by the United States manufacturer (Genentech Inc). Following tests that showed neither loss in activity nor microbiological contamination, we clinically proved the efficacy of t-PA stored at -20 degrees C in 10 cases.

Cryopreservation↗
PubMed1990

Effects of tumor necrosis factor alpha on skeletal muscle and Walker 256 carcinosarcoma protein metabolism studied in vivo.

Human tumor necrosis factor alpha (TNF) inhibits tumor growth, but its effects on tumor and skeletal muscle protein metabolism in vivo have not been adequately studied. Walker 256 carcinosarcoma growth rate was followed over an 11-day period in Sprague-Dawley rats. Tumor-bearing rats received either saline or 50 micrograms of TNF (Genentech, Inc.) s.c. on day 8 of tumor growth. This single dose of TNF reduced tumor protein growth during a 2-day posttreatment period from 27.6 +/- 4.4 to 10.5 +/- 3.7%/day (mean +/- SE; P less than 0.01). The rate of in vivo incorporation of L-[1-14C]leucine into skeletal muscle protein was significantly increased (P less than 0.05) from 5.1 +/- 0.2%/day in the saline-treated tumor-bearing rats to 7.7 +/- 1.3%/day in the TNF-treated tumor-bearing rats. The latter value was not statistically different from the 9.2 +/- 0.9%/day observed in the tumor-free control animals. TNF administration significantly increased both the total and individual acid-soluble skeletal muscle amino acid concentrations in tumor-bearing rats by an average of 86 +/- 7%, compared to values in saline-treated tumor-bearing rats. Similarly, acid-soluble skeletal muscle 3-methyl-histidine concentrations increased from 66 +/- 14 to 113 +/- 19 pmol/g protein (P less than 0.05). Tumor protein synthesis in the TNF-treated group was 50% greater than in the saline-treated group, whether expressed as %/day (72.7 +/- 9.1 versus 47.9 +/- 4.8; P less than 0.05) or was micrograms/g tumor/min (58.7 +/- 7.7 versus 40.7 +/- 4.5; P less than 0.05). In contrast, estimated tumor protein degradation rates were increased by over 200% in the TNF-treated rats, compared to the values in the saline-treated rats [62.1 +/- 10.7 versus 20.3 +/- 6.0%/day (P less than 0.01) and 50.0 +/- 8.9 versus 17.5 +/- 5.4 micrograms/g tumor/min (P less than 0.01)]. Thus, TNF appears to stimulate tumor protein degradation more than protein synthesis, explaining the overall decrease in tumor growth.

Amino Acids↗
PubMed1988

Characterization of human recombinant tumor necrosis factor-alpha antiproliferative effects on human cells in culture.

TNF is a macrophage-derived polypeptide known to cause hemorrhagic necrosis of transplanted tumors and is cytotoxic or cytostatic to a variety of malignant human cells in vitro. However, little is known about its mechanism of antiproliferative activity. Human cervical carcinoma (ME-180) cells in log-phase were treated with various doses of rTNF (from Genentech, Inc., Sp. Act. 5.7 x 10(7) U/mg) for 72 hours. Fifty percent inhibition of cell growth was obtained at a dose of 1000 U/ml (ID50). An identical ID50 was obtained for confluent cells. Maximal antiproliferative effects were observed only with 72 hours continuous exposure to rTNF. Exposure of cells to an ID50 dose for 12 hours or less resulted in no antiproliferative effect; similar to results obtained with murine TNF. The incorporation of [3H] uridine and [3H] thymidine was reduced by 25 and 40% respectively by 24 hours after TNF treatment. [3H] uridine incorporation rebounded to 170% of controls level 72 hours after TNF addition. There was a transient 40% decrease in [3H] leucine incorporation at 48 hours which recovered to control value by 72 hours. These studies show that TNF can suppress both DNA and RNA synthesis while protein synthesis is only transiently affected. Considering its short plasma half-life (approximately 20 min) in vivo, these studies also suggest that for optimal antiproliferative effect rTNF should be administered in a fashion which provides sustained drug levels.

2',5'-Oligoadenylate Synthetase↗
PubMed1987

Potentiation by heparin fragments of thrombolysis induced with human tissue-type plasminogen activator or human single-chain urokinase-type plasminogen activator.

The effect of heparin and of two low molecular weight (low Mr) fractions of heparin on thrombolysis with recombinant human tissue-type plasminogen activator (rt-PA, Genentech Inc., So. San Francisco, CA) or human single chain urokinase-type plasminogen activator (scu-PA, Sandoz AG, Basle, Switzerland) was measured in a rabbit jugular vein thrombosis model. Four bolus injections of 200 anti-Factor Xa units/kg body weight of heparin (Liquemine, Hoffmann-La Roche, Basle, Switzerland), of 90 units/kg of CY 216 (Choay, Paris, France) or of 90 units/kg of CY 222 (Choay, Paris, France) were given intravenously, immediately after the start of the infusion of rt-PA or scu-PA and at hourly intervals during their intravenous infusion over 4 hours. The bolus injections resulted in anti-Factor Xa levels in plasma of 5.7 +/- 1.2 units/ml just before the repeat bolus injections of heparin with corresponding values of 3.9 +/- 0.2 units/ml for CY 216 and 1.6 +/- 0.2 units/ml for CY 222. Thrombolysis with 0.25 mg/kg rt-PA was 36 +/- 1 percent (n = 9) in the absence of anticoagulant, 40 +/- 1 percent (n = 7, p less than 0.05) in the presence of heparin, 49 +/- 5 percent (n = 7, p less than 0.02) with CY 216 and 62 +/- 5 percent (n = 7, p less than 0.01) with CY 222.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Tissue plasminogen activator: a new thrombolytic agent.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, contraindications, and dosage and administration of tissue plasminogen activator are reviewed. Tissue plasminogen activator (t-PA) is a serine protease that binds to fibrin-plasminogen complex, catalyzing the conversion of plasminogen to plasmin. Unlike streptokinase or urokinase, t-PA binds slowly, if at all, to free circulating plasminogen. This clot specificity suggests t-PA will not produce a systemic lytic effect; however, clot specificity appears to be dose-related, and concentrations similar to those achieved in recent clinical trials have been associated with hemostatic defects. Most clinical trials have used a recombinant DNA product (rt-PA). In the treatment of acute myocardial infarction, intravenous infusions of rt-PA appear to be more effective than intravenous streptokinase. Similar rates of hemorrhage, reperfusion arrhythmias, and reocculsion have been reported. Contraindications to rt-PA use are similar to those for other thrombolytic agents. Preliminary studies of rt-PA in various thromboembolic disorders are encouraging. Marketing approval of a t-PA product (rt-PA, Activase, Genentech, Inc.) is expected in the United States by mid-1987. Clinical trials suggest that rt-PA is more effective and as safe as intravenous streptokinase in lysing occlusive coronary-artery thrombi; however, safety and efficacy appear to be dose-related, and further study is needed to determine the optimal dose.

Animals↗