PubMed Health⌕ Search

Biomedical subjects

H Brem

Publications and source records attributed to H Brem.

At least 73 records · Page 4Linked to original sources
PubMed1995

The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial.

The results of a multi-institutional phase I trial evaluating the safety of surgically implanted biodegradable 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) impregnated polymer as the initial therapy for malignant brain tumors are reported. This is the first study of locally delivered BCNU and standard external beam radiation therapy (XRT) given concurrently. Twenty-two patients were treated at three hospitals. The entry criteria were: single unilateral tumor focus larger than 1 cm3; age over 18 years; Karnofsky Performance Score (KPS) of at least 60 h; and an intra-operative diagnosis of malignant glioma. Twenty-one of twenty-two patients had glioblastoma multiforme. After surgery, seven or eight BCNU-loaded polyanhydride polymer discs (7.7 mg BCNU each) were placed in the resection cavity. Postoperatively, all patients received standard radiation therapy; none received additional chemotherapy in the first 6 months. Neurotoxicity, systemic toxicity, and survival were assessed. No perioperative mortality was seen. Neurotoxicity was equivalent to that occurring in other series of patients undergoing craniotomy and XRT without local chemotherapy. Systematically, no significant bone marrow suppression occurred, and there were no wound infections. Median survival in this group of older patients (mean age = 60) was 42 weeks, 8 patients survived 1 year, and 4 patients survived more than 18 months. Interstitial chemotherapy with BCNU-polymer with subsequent radiation therapy appears to be safe as an initial therapy. Several long-term survivors in this group of older patients with predominantly glioblastoma suggests efficacy in some patients. Dose escalation and efficacy trials are planned to further evaluate interstitial chemotherapy for the initial treatment of malignant gliomas.

Adult↗
PubMed1995

Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470.

Hemangioma and other angiomatous diseases of childhood are common. Although most lesions are harmless and self-limiting, some are associated with significant morbidity and may be life-threatening. Interferon-alpha, a weak angiogenesis inhibitor, recently has been found to significantly reduce the mortality rate associated with life-threatening hemangiomas. The effectiveness of AGM-1470, a potent inhibitor of angiogenesis derived from the fungal product fumagillin, was tested in a mouse model of hemangioendothelioma. Thirty syngeneic mice were implanted with cells derived from a spontaneous mouse hemangioendothelioma. Tumors formed within 2 to 3 days, and the animals were then treated systemically with AGM-1470 or with saline and vehicle alone. After 22 days, the tumor volume in the saline-treated mice was 7368 +/- 2723 mm3, versus 709 +/- 73 mm3 in the mice that received AGM-1470 (P < .001). Survival was prolonged for the AGM-1470-treated mice, and there was no evidence of drug-related toxicity. All experiments were repeated. In this study, AGM-1470 was safe and highly effective in the treatment of hemangioendothelioma. AGM-1470, and other antiangiogenic agents, may provide safe and effective treatment for hemangioma and other angiomatous diseases.

Animals↗
PubMed1995

Effectiveness of controlled release of a cyclophosphamide derivative with polymers against rat gliomas.

Most malignant gliomas grow despite treatment by standard chemotherapeutic agents. The authors explored the use of an innovative drug, 4-hydroperoxycyclophosphamide (4HC), delivered via a controlled-release biodegradable polymer to determine whether local delivery would enhance efficacy. This drug is an alkylator-type chemotherapeutic agent derived from cyclophosphamide. Unlike the parent drug, which requires activation by hepatic microsomes, 4HC is active in vitro. Two rat glioma cell lines, 9L and F98, were treated in cell culture with medium containing 4HC. Both cell lines were more sensitive to 4HC than to a nitrosourea, BCNU, an agent of established value in the local therapy of gliomas. Ninety Fischer 344 rats implanted with 9L or F98 gliomas were treated with an intracranial polymer implant containing 0% to 50% loaded 4HC in the polymer, and it was found that 20% 4HC-loaded polymers caused minimum local brain toxicity and maximum survival. These polymers were then used to compare the in vivo efficacy of 4HC to BCNU in rats implanted with 9L glioma. Animals with brain tumors treated with 4HC had a median survival span of 77 days compared to the median survival of 21 days in BCNU-treated animals and median survival of 14 days in untreated animals. Long-term survival for more than 80 days was 40% in the 4HC-treated rats versus 30% in the BCNU-treated rats. The polymer carrier used in this study was a copolyanhydride of dimer erucic acid and sebacic acid 1:1, which was able to maintain the hydrolytically unstable 4HC in a stable state for local delivery. Thus, it is concluded that 4HC-impregnated polymers provide an effective and safe local treatment for rat glioma.

Animals↗
PubMed1995

The role of minocycline in the treatment of intracranial 9L glioma.

This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection. Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.

Animals↗
PubMed1995

Differentiating lymphocytic adenohypophysitis from pituitary adenoma in the peripartum patient.

Lymphocytic adenohypophysitis (LAH) is an autoimmune disorder of the pituitary gland with a predilection for the peripartum period and often mimics a pituitary adenoma. We sought to define the clinical, endocrinologic and radiographic characteristics differentiating peripartum LAH from pituitary adenoma to enable the use of noninvasive diagnosis and appropriate therapy. From published reports and our own case, the clinical histories and laboratory and radiographic studies of 45 patients fulfilling the diagnosis of peripartum LAH were reviewed. History of infertility or menstrual irregularity, symptomatology, endocrinologic evaluation, diagnostic imaging and associated medical conditions were analyzed. For comparison, 806 patients with pituitary adenoma and pregnancy from published series were evaluated. The spontaneous pregnancy rate in pituitary adenoma patients was 2.4% vs. 100% in LAH patients. Visual disturbances and headaches were significantly more frequent in patients with LAH. Prolactin levels were significantly lower in patients with LAH than in those with pituitary adenomas (34.6 +/- 46.3 [SD] vs. 393.0 +/- 300.4, P < .0001). Abnormalities in thyroid and/or adrenal function were also more common in patients with LAH (57.5% vs. 2.5%, P < .001). There were no distinguishing characteristics on radiographic studies. History and endocrinologic evaluation can differentiate between LAH and pituitary adenoma in the peripartum patient.

Autoimmune Diseases↗
PubMed1995

New delivery systems for brain tumor therapy.

Therapy of brain tumors has been limited by lack of effective methods of drug delivery. Systemic administration often fails to achieve therapeutic concentrations of drugs within intracranial tumors despite toxic systemic levels. This article discusses new methods for delivering therapeutic agents to brain tumors, including intra-arterial, intrathecal, intraventricular, and interstitial administration techniques.

Adult↗
PubMed1995

Intratumoral chemotherapy.

In an effort to improve survival from malignant gliomas, investigators have used intratumoral chemotherapy protocols to deliver high doses of tumoricidal agents directly to the brain. Theoretically, these infusions bypass the blood-brain barrier, minimize systemic drug levels and the side effects of chemotherapy, and achieve prolonged elevations of intracerebral chemotherapeutic agents relative to those obtainable by systemic administration. Almost all major classes of chemotherapeutic agents have been examined as possible intratumoral therapies via delivery approaches ranging from simple intratumoral injections to implantable computer-driven constant infusion pumps and biodegradable polymer matrices. In this review, we summarize the major clinical trials and experimental investigations underlying the development of intratumoral chemotherapy as a treatment for gliomas.

Animals↗
PubMed1994

Inhibition of tumor angiogenesis.

The exponential growth of solid tumors depends upon induction of new vessel growth, a process mediated by diffusable angiogenic factors produced by tumor cells. By inhibiting angiogenesis, it is now possible to modulate tumor growth and metastasis in laboratory animals. The first described inhibitor of angiogenesis was a protein derived from cartilage. Other important classes of antiangiogenic agents include angiostatic steroids combined with heparin or heparin derivatives, and the synthetic derivatives of fumigallin. As the mechanisms of action of these and other angiostatic agents are being elucidated, it is becoming apparent that many modulators of collagen metabolism inhibit angiogenesis and may offer clinically useful anticancer treatments. Minocycline and other tetracycline derivatives with anticollagenase properties have been shown to be potent inhibitors of angiogenesis. These agents, when administered with other standard cancer therapies, help prolong survival in laboratory animals with solid tumors. Further studies of these biologic response modifiers of tumor progression are under way in the hope that they will offer effective new treatments for cancer in humans.

Animals↗
PubMed1994

Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents.

The ability of TNP-470, a synthetic analog of fumagillin which has been described as an anti-angiogenic agent, to potentiate cytotoxic cancer therapies was investigated in vivo in the murine FSaIIC fibrosarcoma and the Lewis lung carcinoma. TNP-470 was more toxic toward FSaIIC tumor cells from tumors treated in vivo than toward bone-marrow CFU-GM from the same animals. TNP-470 had a dose-modifying effect on the toxicity of cyclophosphamide toward FSaIIC tumor cells which amounted to an 8-fold increase in tumor-cell killing at a cyclophosphamide dose of 500 mg/kg. Treatment with TNP-470 and minocycline increased the permeability of the FSaII fibrosarcoma in vivo to the fluorescent dye Hoechst 33342 and increased the killing of both the bright and the dim tumor cells by cyclophosphamide. TNP-470, especially in combination with minocycline, formed a highly effective modulator combination for treatment of the Lewis lung carcinoma with cytotoxic cancer therapies against primary and metastatic disease. The combination of TNP-470/minocycline and cyclophosphamide led to 40 to 50% long-term survivors in Lewis-lung-carcinoma-bearing animals. Our results indicate that the use of anti-angiogenic modulators in cancer therapy is a very promising area for further study.

Animals↗
PubMed1994

Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma.

Taxol is a novel antitumor agent with demonstrated efficacy against ovarian, breast, and non-small cell lung cancers in Phase II clinical trials, but which has been shown not to cross the blood-brain barrier. To adapt taxol as a therapy for brain tumors, we have incorporated it into a biodegradable polyanhydride matrix for intracranial implantation and evaluated this formulation in a rat model of malignant glioma. Fischer 344 rats bearing intracranial 9L glioma tumors were treated with 10 mg poly[bis(p-carboxyphenoxy)propane-sebacic acid] (20:80) copolymer discs, containing 20-40% taxol by weight, 5 days after tumor implantation. The taxol-loaded polymers doubled (38 days, 40% taxol loading, P < 0.02) to tripled (61.5 days, 20% taxol loading, P < 0.001) the median survival of rats bearing tumor relative to control rats (19.5 days). Drug loadings of 20-40% taxol by weight released intact taxol for up to 1000 h in vitro. In rats followed up to 30 days postimplant, the polymer maintained a taxol concentration of 75-125 ng taxol/mg brain tissue (100-150 microM taxol) within a 1-3-mm radius of the disc. At points more distant from the disc (up to 8 mm away, the size limit of the rat brain), the polymer maintained a taxol concentration of greater than 4 ng taxol/mg brain tissue (5 microM). We conclude that taxol shows promise as a therapy for malignant glioma when delivered interstitially from a biodegradable polymer.

Animals↗
PubMed1994

Covalent coupling of methotrexate to dextran enhances the penetration of cytotoxicity into a tissue-like matrix.

For antitumor agents introduced directly into the intracranial space, the extent of penetration into tissue, and hence the effectiveness of therapy, depends on the rate of drug elimination from the tissue. To test the hypothesis that slowly eliminated agents would penetrate further through tissues, methotrexate (MTX)-dextran conjugates were produced by covalently linking MTX to dextran through a short-lived ester bond (MTX-ester-dextran; t1/2 approximately 3 days in buffered saline) and a longer-lived amide bond (MTX-amide-dextran; t1/2 > 20 days in buffered saline). The ability of these agents to kill cells and to penetrate through tissue was evaluated using: (a) human brain tumor (H80) cells in a standard format; (b) H80 cells in a novel three-dimensional format that mimics many characteristics of intracranial tumors; and (c) 9L gliosarcoma in the rat brain. Penetration into three-dimensional tissue-like matrices was performed by suspending H80 cells in agarose gels within a hollow fiber that was permeable to MTX but not dextran and injecting MTX or MTX-dextran conjugates into one end of the fiber. The cytotoxicity of MTX-ester-dextran and MTX-amide-dextran against H80 was equivalent to unmodified MTX (50% inhibitory concentration, approximately 0.01 microgram/ml). When released from a biodegradable polyanhydride polymer matrix, MTX and MTX-dextran conjugates retained their ability to inhibit dihydrofolate reductase activity. When MTX or MTX-dextran was diffused into the three-dimensional tumor cell matrix for 10 days, cytotoxic activity penetrated > 2 cm for MTX-amide-dextran and approximately 1 cm for MTX or MTX-ester-dextran; this enhanced penetration correlated with the stability of the MTX-dextran linkage. Intracranial polymeric delivery of MTX or MTX-amide-dextran to rats with intracranial 9L gliosarcoma produced modest but significant increases in survival; conjugation of MTX to dextran appeared to shift the dose-response curve to a lower dosage.

Animals↗
PubMed1994

Endothelial differentiation in intracerebral and subcutaneous experimental gliomas.

Blood-brain barrier (BBB) properties of endothelial cells have on impact on brain tumor behavior, diagnosis, and response to therapy. Biochemical BBB properties are expressed by endothelial cells within intracerebral (IC) gliomas but little is known regarding the expression of BBB-associated proteins within gliomas established subcutaneously (SC), a site that is frequently used in experimental glioma models. We compared the expression of two BBB proteins, glucose transporter type-1 (Glut1) and endothelial barrier antigen (EBA), in IC and SC rat 9L and F98 gliomas. The percentage of microvessels with immunohistochemically-detectable Glut1 and EBA in IC 9L tumors (31-98%) contrasted with that found in SC 9L tumors (0-3.9%) (P < 0.0001). Likewise, the percentage of immunohistochemically-positive vessels in IC F98 tumors (35-66%) differed markedly from that in SC F98 tumors (0%) (P < 0.0001). These differences were not explained by effects of tumor location on vessel density or tumor histology. These findings demonstrate that the peritumoral environment influences endothelial differentiation within glial tumors and suggest that glioma cells maintain but do not induce the expression of barrier properties in vessels that infiltrate tumor from surrounding tissue.

Animals↗
PubMed1994

Transforming growth factor-alpha-Pseudomonas exotoxin fusion protein (TGF-alpha-PE38) treatment of subcutaneous and intracranial human glioma and medulloblastoma xenografts in athymic mice.

Epidermal growth factor receptor (EGFR) is amplified or overexpressed in many malignant gliomas and other primary brain tumors but is low or undetectable in normal brain. In the present study, this differential expression has been exploited for targeted brain tumor therapy using a TGF-alpha-Pseudomonas exotoxin recombinant toxin, TGF-alpha-PE38. In vitro experiments demonstrate that the cytotoxicity of this fusion protein is primarily determined by tumor EGFR expression and that TGF-alpha-PE38 cytotoxicity is abolished by pretreatment with excess epidermal growth factor. Treatment with i.p. TGF-alpha-PE38 in nude mice bearing glioblastoma or medulloblastoma s.c. xenografts produced tumor regression and growth delay. For intracranial xenograft implants treated with i.p. TGF-alpha-PE38, significant increases in median survival were noted only for tumors with the highest EGFR expression. However, intracranial tumors treated with a single intratumoral injection of TGF-alpha-PE38 showed increased survival in all xenografts tested. These results indicate that TGF-alpha-PE38 is active against primary human brain tumors ranging from moderate to high EGFR expression. For intracranial tumors, however, the higher survival rates produced by intracranial injection of TGF-alpha-PE38 than by continuous i.p. administration suggest that increased drug clearance or impaired drug delivery reduces the efficacy of systemic TGF-alpha-PE38. Direct delivery of TGF-alpha-PE38 into brain tumors by controlled-release biodegradable polymers or intratumoral implanted catheters, or intrathecal administration into the colony stimulating factor of patients with leptomeningeal metastasis, may represent clinically useful applications of recombinant toxin therapy in tumors with high EGFR expression.

Animals↗
PubMed1994

In vivo versus in vitro degradation of controlled release polymers for intracranial surgical therapy.

Intracranial studies to analyze the degradation kinetics of the bioerodible polymer poly[bis(p-carboxyphenoxy)propane-sebacic acid] [p(CPP-SA) 20:80] copolymer wafers were conducted in a rat model. Rats were separated into four groups: those receiving 1) polymer, 2) polymer loaded with the chemotherapeutic agent BCNU, 3) drug-loaded polymer with previous tumor implantation, and 4) polymer and an absorbable hemostatic material. A polymer wafer was surgically implanted into the brain of each animal. Residual polymer was harvested at varying times for chromatographic analysis. In vitro effects of pH, mixing, and water availability on degradation were also studied. The results of in vitro and in vivo studies were compared to understand the behavior of polymers in a clinical setting. We found that degradation of p(CPP-SA) initially occurred more slowly in vivo than in vitro. The presence of BCNU, tumor, and absorbable hemostatic material did not affect the ultimate time of polymer degradation in vivo, and the intrinsic polymer degradation time of 1 mm thick p(CPP-SA) 20:80 disks in vivo was 6-8 weeks.

Animals↗
PubMed1994

Cytotoxicity of taxol in vitro against human and rat malignant brain tumors.

Taxol is a novel antitumor alkaloid that has shown clinical activity against several tumors, including ovarian and breast carcinoma and melanoma. To evaluate taxol's potential as a therapy for malignant brain tumors, we measured the sensitivity of four human (U87, U373, H80, and D324) and two rat (9L, F98) brain-tumor cell lines to taxol. The cells were exposed to taxol in vitro using a clonogenic assay. Log cell kill (LD90) occurred at concentrations of 42 (9L), 25 (F98), 19 (H80), 7.2 (U373), 9.1 (U87), and 3.9 nM (D324) when cells were continuously exposed to taxol for 6-8 days. The human cell lines were uniformly more sensitive to taxol than were the rat lines. The duration of exposure had a significant effect on taxol's cytotoxicity. When cells were exposed to taxol for 1 h the LD90 increased to 890 nM for the 9L rat line and 280 nM for the human U373 line. On the basis of these results, we conclude that taxol has significant potency in vitro against malignant brain tumors and that the activity occurs at concentrations of taxol that have previously been shown to be effective for several tumors against which the drug is currently being evaluated clinically.

Animals↗
PubMed1994

Detection of biological activity in the cerebrospinal fluid of patients with central nervous system tumors.

Tumor markers for brain tumors are important for initial diagnosis and monitoring of treatment. We used a modification of the phagokinetic track assay, which measures the migration of cells across a coverslip that is coated with colloidal gold, to assess whether the CSF from patients with brain tumors and other non-neoplastic neurological disorders altered the migration of Balb/c 3T3 fibroblasts. We found that CSF from patients with brain tumors stimulated the migration activity at a significantly higher level than did CSF from patients without tumors (mean migration activity: 65 +/- 9% for CSF from 113 patients with brain tumors; 14 +/- 4% for 44 patients with non-neoplastic CNS disease; and 9 +/- 1.2% for 54 patients with metabolic or other disorders). Thus the ability of CSF to stimulate migration of 3T3 cells appears to be a promising approach to detecting, understanding and following the activity of brain tumors.

3T3 Cells↗
PubMed1994

Chromosome abnormalities in meningeal neoplasms: do they correlate with histology?

Thirty-three meningeal neoplasms were karyotyped, and the results were compared with histologic features. Thirteen neoplasms had no discernible abnormality or sex chromosome loss only; nine had monosomy or structural abnormality involving only chromosome 22; and 11 had other chromosome abnormalities with or without chromosome 22 involvement. Histologic evidence of invasion was not associated with an abnormal karyotype in the three angioblastic tumors examined. All seven fibroblastic meningiomas had abnormal karyotypes, with monosomy 22 the most common change. Abnormal karyotypes were detected in 76% of syncytial and 55% of transitional meningiomas. When these results were combined with those from 259 meningeal tumors reported since 1987, abnormal karyotypes were detected in at least half of all histologic types. Chromosome changes secondary to those involving chromosome 22 may indicate additional areas of the genome that play a role in tumor progression. In the combined series, chromosome losses were most frequently observed in meningiomatous and transitional histologies; chromosomes 1, 6, 14, 18, and Y each were lost in 10 or more meningiomas, whereas only chromosome 20 was gained at the same frequency. Structural abnormalities most frequently involved chromosome 1. These changes are distinctly different from those observed in other common intracranial neoplasms, specifically astrocytic neoplasms.

Adult↗