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Biomedical subjects

S A Sherwin

Publications and source records attributed to S A Sherwin.

At least 37 records · Page 2Linked to original sources
PubMed1986

Phase I trial of recombinant interferon gamma by 1-hour i.v. infusion.

Fifteen patients with advanced malignancy were treated with recombinant interferon gamma (rIFN-gamma) (specific activity approximately 2 X 10(7) units/mg, purity greater than 99%) given by 1-hour iv infusion three times a week for 6 weeks, at fixed dose levels of 0.1, 0.5, 1.0, or 2.0 mg/m2/day. The common side effects were constitutional symptoms, including fever, chills, myalgias, and headache, but these were less severe than those observed following daily 6-hour iv infusions. Significant changes in blood cell counts and routine serum chemistries were not observed, but there was a dose-dependent increase in serum triglyceride levels. The maximum safely tolerated dose achieved was 1.0 mg/m2/day. Peak serum interferon levels occurred at the midpoint of the infusion and were dose-dependent. rIFN-gamma was rapidly cleared from serum and no detectable activity was found 2 hours after the infusion. Two patients, both with B-cell malignancies, showed objective evidence of tumor regression during the treatment. Treatment was associated with an increase in serum levels of beta 2-microglobulin and the H2O2 secretory capacity of peripheral blood monocytes. We conclude that rIFN-gamma administered by short iv infusion can induce biological activities and causes less toxicity than when given by prolonged iv infusion.

Adult↗
PubMed1986

Phase I study of i.v. administered recombinant gamma interferon in cancer patients.

We report a phase I study of the biological effects, tolerance, and pharmacokinetics of 6- and 24-hour iv infusions of recombinant interferon-gamma (rIFN-gamma) in cancer patients. Twenty-one patients received the 6-hour iv infusion regimen at doses ranging from 0.016 to 0.65 mg/m2/day. Forty-one patients received the 24-hour iv infusion regimen at doses ranging from 0.01 to 0.05 mg/m2/day. Fever and flu-like symptoms were the most common side effects and were seen at all dose levels. The maximum tolerated dose was 0.16 mg/m2 for the 6-hour regimen and 0.01 mg/m2/day for the 24-hour regimen. A dose-dependent granulocytopenia was observed at doses greater than or equal to 0.05 mg/m2/day. A marked increase in beta2 microglobulin occurred by Day 5 of treatment in almost all patients, regardless of the dose level. Consistent serum levels of rIFN-gamma were achieved only at doses of 0.325 mg/m2/day of the 6-hour infusion. The mean serum concentrations at this dose ranged from 18 to 83 units/ml as measured by bioassay (0.64-2.4 ng/ml by enzyme-linked immunoassay). Antibody against rIFN-gamma did not develop in any patient. During the short period of evaluation of this study, one patient with renal cell carcinoma achieved a partial response, and three patients with renal cell (two) and lung carcinoma (one), respectively, achieved minor responses. This study will form the framework for phase II efficacy trials of iv rIFN-gamma.

Adult↗
PubMed1985

Transforming growth factor (TGF) activity in human urine: synergism between TGF-beta and urogastrone.

Human urine contains an acid and heat stable peptide with an apparent molecular weight of 8,000-10,000 that, in the presence of urogastrone (EGF), induces the anchorage-independent growth of nontransformed cells in semisolid media. This nonmitogenic growth-modulating activity does not compete with EGF for binding to EGF membrane receptor sites and can be resolved from EGF by high-performance liquid chromatography. The urine-derived growth factor has been purified more than 10,000-fold and shares many biochemical properties with and is functionally related to the B class of TGFs isolated from transformed cells and non-neoplastic tissues. The low molecular weight anchorage-independent growth-stimulating activity universally present in human urine is a result of the synergistic interaction of this urine-derived TGF-beta and urogastrone.

Animals↗
PubMed1985

A phase I trial of recombinant gamma interferon in patients with cancer.

A total of 11 patients were treated on an escalating, single dose trial of recombinant gamma interferon (rIFN-gamma), 6 patients by the i.m. and 5 patients by the i.v. route of administration. Dose ranges within each individual were from 0.05 mg/m2 of IFN (1 mg greater than or equal to 10 X 10(6) units of IFN) escalating to 10 mg/m2. All dosages were delivered twice weekly and the i.v. dose was infused over 5 min. The most common toxicities encountered included fever, chills, fatigue, anorexia, and granulocytopenia. The influenza-like symptoms were very similar to those encountered with IFN-alpha but were generally less severe. The granulocytopenia was dose-related and transient with recovery generally seen within 48-72 h following administration of rIFN-gamma. Absolute granulocyte counts only rarely dropped below 1000 mm3. Hepatotoxicity was not observed. IFN levels were determined by both a bioassay and an enzyme-linked immunosorbent assay. By the i.v. route, the peak level of IFN activity could usually be seen at completion of the infusion with a serum half-life of 30 min. By the i.m. route, the peak level of serum activity was generally detected between 4-8 h with a serum half-life of 4.5 h after the initial elimination phase. Peak IFN levels appeared to correlate with maximum toxicity. One patient with melanoma had a 25% reduction in a cutaneous lesion, but there were no other minimal, partial, or complete responses.

Drug Evaluation↗
PubMed1985

Administration of recombinant interferon gamma to cancer patients enhances monocyte secretion of hydrogen peroxide.

Recombinant interferon gamma (rIFN-gamma) activates macrophage antimicrobial and antitumor functions and related metabolic processes, including secretion of reactive oxygen intermediates in mice and in cultured mouse and human macrophages. To look for similar actions in man, we monitored the H2O2 secretory capacity of monocytes from cancer patients receiving intravenous rIFN-gamma at 0.1, 0.5, or 1.0 mg/m2 of body area over 6 hr daily or over 1 hr on alternate days. Monocytes taken just before the first infusion served as controls and were comparable to normal donor monocytes in secretion of H2O2. Monocytes from 11 of the 13 subjects (85%) studied through 20 treatment cycles responded to rIFN-gamma with elevation in H2O2 secretion in greater than or equal to 67% of the tests conducted greater than 1 hr after the start of treatment. Five of the five subjects tested had monocytes with diminished H2O2 secretory capacity when tested immediately after a 1-hr infusion of rIRN-gamma, at which time the amount of adherent mononuclear cell protein recovered from the blood averaged only 24% of the control. At all other times tested (from 6 hr to 5 days after infusion) combined results for all subjects showed enhancement of H2O2 releasing capacity. Statistically significant mean increases ranged from 1.4- to 2.8-fold above the control and included the sets in which monocytes collected 24 hr following a single infusion were assayed the same day or the next. By the criterion of enhanced H2O2 secretory capacity, the ability of rIFN-gamma to activate mononuclear phagocytes is manifest upon its administration to patients with advanced malignancy.

Adult↗
PubMed1985

Comparison of growth factors functionally related to epidermal growth factor in the urine of normal and human tumor-bearing athymic mice.

Urine from nude mice contains epidermal growth factor (EGF) and a minor acid-stable component with an apparent molecular weight of 20,000, which competes with EGF for binding to EGF membrane receptors and which promotes colony formation by normal rat kidney cells in soft agar. The levels of this Mr 20,000 urine-derived growth factor are increased approximately 4- to 10-fold in nude mice bearing tumors following s.c. injection of cultured human tumor cells. Following removal of the primary tumor, the concentration of this factor is reduced to basal levels, and thus, elevated levels of this growth factor appear to be dependent on tumor burden. The Mr 20,000 urinary component is separable into four EGF competing activities by high-performance liquid chromatography; the major species is immunologically related to mouse submaxillary gland EGF and therefore appears to be of host origin. However, in addition to elevated levels of host growth factor, urine from tumor-bearing mice also contains transforming growth factor activity in amounts comparable to that released by the tumor cells in culture. The tumor-derived urinary transforming growth factor activity is immunologically unrelated to EGF but is immunoreactive with an antiserum to transforming growth factor-alpha. We propose that the nude mouse may be a useful model to examine the role of both host- and tumor-derived growth factors in tumorigenesis and the usefulness of these factors as biological markers of response to therapy and tumor progression.

Animals↗
PubMed1985

Pharmacokinetics, single-dose tolerance, and biological activity of recombinant gamma-interferon in cancer patients.

We report a clinical study of the pharmacokinetics, toxicity, and biological activity of i.v.- and i.m.-administered recombinant gamma-interferon (rIFN-gamma) consisting of 143 amino acids. Ten patients with metastatic cancer were given rIFN-gamma at doses of 0.01 to 2.5 mg/sq m by alternating i.m. and i.v. bolus injections with a minimum intervening period of 72 h. After i.v. administration, rIFN-gamma was cleared monoexponentially with a short half-life of 25 to 35 min as determined by bioassay and enzyme immunoassay. After i.m. injection, a longer half-life of 227 to 462 min was measured by enzyme immunoassay. Serum titers were detected by bioassay only at high doses, suggesting partial loss of antiviral activity at the i.m. site. However, other biological effects were retained as evidenced by fever, chills, and fatigue after both routes of administration and granulocytopenia after i.m., but not i.v., doses. Two of ten patients showed objective evidence of tumor regression. These data suggest that further studies with i.m. as well as prolonged i.v. infusions of rIFN-gamma are indicated.

Half-Life↗
PubMed1984

Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon.

We report the results of a trial of recombinant leukocyte A interferon in previously treated patients with non-Hodgkin's lymphoma who were no longer responsive to chemotherapy. Patients received recombinant leukocyte A interferon (50 X 10(6) U per square meter of body-surface area) by intramuscular injection three times weekly for three months or longer. Forty-five patients were enrolled in the study, and 37 were evaluated for a response. Thirteen of 24 (54 per cent) evaluable patients with low-histologic-grade non-Hodgkin's lymphoma had objective responses (nine partial responses and four histologically confirmed complete responses). Two of six (33 per cent) with intermediate-grade lymphoma responded (one partially and one completely), and one of seven (14 per cent) with high-grade lymphoma had a partial response. The median duration of responses was eight months. Four of the five complete responders have continued to receive maintenance interferon and have been in complete remission for 3, 7, 9, and 12 months, respectively; one had a recurrence at a site of previous disease seven months after interferon had been stopped. Side effects were noted in most patients. All 16 responders had been heavily pretreated with combination chemotherapy, including doxorubicin in 8 of the 16. These results suggest that recombinant leukocyte A interferon may be an effective new therapy for some patients with low- and intermediate-grade non-Hodgkin's lymphoma.

Adult↗
PubMed1984

Atypical tumor lysis syndrome in a patient with T cell lymphoma treated with recombinant leukocyte interferon.

Biochemical and clinical signs of tumor lysis syndrome developed in a 57-year-old man with recurrent T cell lymphoma during therapy with recombinant leukocyte A interferon. When therapy was interrupted due to thrombocytopenia and later resumed, biochemical changes compatible with tumor lysis recurred. This is the first case of tumor lysis syndrome observed during therapy with a biologic response modifier, a new class of agents entering cancer clinical trials. The atypical features of the clinical presentation and possible implications of these observations are discussed.

Humans↗
PubMed1984

Recombinant alpha interferon in retreatment of two patients with pulmonary lymphoma. Dramatic responses with resolution of pulmonary complications.

Two patients with advanced lymphoma involving the lungs that was resistant to chemotherapy had an initial excellent response to interferon therapy. After two months of stable disease, alpha interferon A therapy was discontinued, with relapse of a few months later. Both patients had extensive pulmonary involvement with relapse of the lymphoma, and both showed a dramatic response to retreatment with alpha interferon A. Unusual interferon-related pulmonary complications were observed in one patient, and their management is detailed.

Adrenal Cortex Hormones↗
PubMed1984

Distinct high-performance liquid chromatography pattern of transforming growth factor activity in urine of cancer patients as compared with that of normal individuals.

Reverse-phase high-performance liquid chromatography (HPLC) performed on urine from cancer patients and normal controls revealed the presence of seven chromatographically distinct peaks of transforming growth factor (TGF) activity, as measured by colony formation of normal rat kidney cells in soft agar. Comparison of urines from normal donors and cancer patients showed no differences in EGF (epidermal growth factor)-dependent beta-TGF-like activity but did reveal distinct patterns of EGF-related, EGF-independent alpha-TGF-like activity. All urine samples contained at least two chromatographically distinguishable forms of EGF-dependent TGF activity, eluting from HPLC as broad peaks with 30 and 43% acetonitrile. The remaining five TGFs eluted as sharp peaks with 32, 34, 35, 37, and 38% acetonitrile, demonstrated EGF-competing activity, and thus were functionally related to EGF. Two of the five EGF-related TGFs were consistently elevated only in the urine of cancer patients and eluted with 32% (TGFA) and 37% (TGFD) acetonitrile Two of the other EGF-related TGFs, eluting with 34% (TGFB) and 35% (TGFC) acetonitrile, were commonly found in both normals and cancer patients. The fifth EGF-related TGF, TGFE, eluting with 38% acetonitrile, was found only in normal donor specimens. TGFA corresponded to the unique Mr 30,000 TGF activity previously identified only in the urine of cancer patients. These observations demonstrate that cancer patients produce high levels of EGF-related TGF activities which can be readily distinguished, using reverse-phase HPLC, from EGF-related TGFs produced by normal individuals. Using a solid-phase competitive radioreceptor binding assay for EGF, we demonstrated that quantitation of EGF-competing activity is as sensitive and effective as the soft-agar colony formation assay for distinguishing HPLC profiles of urinary TGF from cancer patients versus that from normal individuals.

Adolescent↗
PubMed1984

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia.

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B-derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.

Antibodies, Monoclonal↗
PubMed1984

A preliminary Phase I trial of partially purified interferon-gamma in patients with cancer.

Thirty-three patients were treated in an escalating single-dose trial of partially purified nonrecombinant interferon-gamma (IFN-gamma). The first seven patients received intramuscular injections of IFN-gamma in doses up to 20 X 10(6) units/m2. When it became clear that these patients had no detectable antiviral activity in their serum, subsequent patients were treated by the intravenous route of administration, generally with 2-h infusions. A total of 26 patients received the agent intravenously in single escalating doses ranging from 0.2 to 60 X 10(6) units/m2, on a twice-weekly schedule for 4-6 weeks. The most common toxicities encountered included fever, chills, fatigue, anorexia, and occasional nausea and vomiting. No myelosuppression or hepatic toxicity was observed. A maximum tolerated dose for single-dose intravenous administration was defined as 50 X 10(6) units/m2 on the basis of unacceptable fatigue and prolonged systolic hypotension. Antiviral activity was detected in the serum following doses greater than 2 X 10(6) units/m2 when the IFN-gamma was administered intravenously. No evidence of antitumor activity was seen in this Phase I trial, although the treatment regimen employed did not lead to high or prolonged levels of serum IFN activity in the majority of patients. An accurate assessment of the antitumor activity of this particular IFN-gamma preparation will require Phase II trials employing multiple-treatment regimens.

Drug Evaluation↗
PubMed1983

The treatment of cancer patients with human lymphoblastoid interferon. A comparison of two routes of administration.

Highly purified human lymphoblastoid interferon (HLBI) derived from virus-stimulated Namalwa cells was administered by 6-h IV infusion or IM injection to 40 patients with a variety of disseminated malignancies refractory to standard therapy. Each patient received doses escalating from 0.1 to 50 X 10(6) U for up to 5 weeks. Extensive monitoring for clinical effect, toxicity, and pharmacokinetics has revealed higher peak serum interferon levels and somewhat more pronounced systemic toxicity for the IV than for the IM route of administration. Objective evidence of tumor regression was observed in two patients receiving HLBI IV.

B-Lymphocytes↗
PubMed1983

Recombinant leukocyte A interferon in advanced breast cancer. Results of a phase II efficacy trial.

Nineteen patients with advanced refractory metastatic breast cancer no longer responsive to chemotherapy were treated in the first phase II efficacy trial of recombinant leukocyte A interferon (IFL-rA), a highly purified single molecular species of alpha interferon prepared by recombinant DNA methods. Patients received a previously determined maximum tolerated dose for this agent (50 X 10(6) U/m2 body surface area) by intramuscular injection three times weekly for up to 3 months. The symptoms of toxicity observed in this trial resemble those previously reported for alpha interferons and include fever, chills, fatigue, anorexia, and leukopenia. All patients required dose reductions, most often for reasons of severe fatigue. Of the 17 patients evaluable for tumor response, one patient had stable disease and 16 had evidence of tumor progression. We conclude that IFL-rA is not an active agent in the treatment of advanced, refractory breast cancer when used at a maximum tolerated dose on this treatment schedule.

Adult↗
PubMed1983

Effects of recombinant interferon-alpha on immune function in cancer patients.

Patients with a variety of malignancies were treated in phase I clinical trials of recombinant leukocyte A interferon (IFL-rA) schedules consisting of either twice-daily doses for 28 days (48 patients) or three times weekly for 28 days (86 patients). Extensive monitoring of several immune functions was done on these patients, with rigorously standardized assays and determination of inherent variability of function for each individual. The assays performed were natural killer (NK) cell cytotoxicity, monocyte cytostatic activity, lymphoproliferative responses to concanavalin A (con A) and mixed leukocyte culture, and an analysis of changes in leukocyte populations as determined using a panel of monoclonal antibodies and flow cytometry. No appreciable increase in NK activity was observed on any of the treatment regimens, and an unexpected observation was the depression of activity in a substantial proportion (30%) of patients. In contrast, monocyte function, as measured in an assay of growth inhibition of tumor target cells, was found to be elevated in 70% of the patients. Lymphoproliferative responses were depressed in most patients in response to both con A and the mixed leukocyte culture. Cell surface marker studies revealed an increase in the percentage of OKT10 positive cells in the majority of patients studied and a transient increase in cells reacting with the antibody MO2. The data have been analyzed in terms of their relationship to dose and schedule of administration, and the depression of NK activity was shown to be greatest at the highest doses and more frequent schedule of administration.

Clinical Trials as Topic↗
PubMed1983

High-molecular-weight transforming growth factor activity in the urine of patients with disseminated cancer.

Urine from 22 patients with a variety of disseminated cancers and from an equivalent number of nonmalignant controls of similar age and sex was tested for the presence of transforming growth factor (TGF) activity as measured by the ability to promote the growth in soft agar of nontransformed indicator cells. Cancer patients included those with carcinomas of the lung, breast, colon, and ovary, as well as melanomas and sarcomas. The nonmalignant controls included both normals and individuals with a variety of inflammatory and infectious disorders. Aliquots of unfrozen urine were acid extracted, chromatographed on a Bio-Gel P-30 column, and then tested for TGF activity using normal rat kidney fibroblasts and epidermal growth factor (EGF)-competing activity with human carcinoma A431 cells. These assays revealed that a high-molecular-weight TGF activity (Mr 30,000 to 35,000) which coelutes with EGF-competing activity was present in 18 of 22 cancer patients but present in only five of 22 nonmalignant controls (p less than 0.01). In contrast, a low-molecular-weight TGF activity (Mr 6000 to 8000) which does not coelute with EGF-competing activity was found in all urines tested. These results indicate that an EGF-related, high-molecular-weight TGF activity is found in the urine of cancer patients and may be a useful tumor marker. Unlike other tumor markers described previously, high-molecular-weight TGF activity has a biological activity which is related to the expression of the transformed phenotype.

Binding, Competitive↗