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Biomedical subjects

M J Chang

Publications and source records attributed to M J Chang.

At least 37 records · Page 2Linked to original sources
PubMed1997

Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity.

Interleukin-1alpha (IL-1alpha) has potent acute antitumor activity in vivo and can enhance the efficacy of chemotherapeutic drug-mediated antitumor responses. Studies were undertaken to examine the ability of IL-1alpha to enhance the activity of cyclophosphamide (CTX) administered in combination with carboplatin. To determine the in vivo effect of IL-1alpha, CTX and/or carboplatin, mice bearing 14-day RIF-1 tumors were treated on day 0 with a concurrent i.p. injection of varying doses of CTX (5-150 mg/kg), human IL-1alpha (125 microg/kg), and carboplatin (50 mg/kg) and examined 24 h later for the surviving fraction by the in vivo excision clonogenic-tumor-cell assay. Even at the lowest doses of CTX, IL-1alpha significantly enhanced the clonogenic tumor cell kill when compared to treatment with CTX alone. When carboplatin was added to the treatment schema, significantly greater clonogenic cell killing and tumor regrowth delay were observed as compared to any agent alone or a two-drug combination (CTX/IL-1alpha or CTX/carboplatin). Significant enhancement was observed even at low doses of CTX in combination with carboplatin and IL-1alpha. The interaction between the three-drug combination was found to be synergistic as determined by the median dose effect with significant dose reduction apparent for IL-1alpha and CTX when used in this combination. These results demonstrate that IL-1alpha can synergistically enhance the antitumor efficacy of CTX and the combination of CTX and carboplatin.

Animals↗
PubMed1997

Cutaneous involvement in polyvinylpyrrolidone storage disease: a clinicopathologic study of five patients, including two patients with severe anemia.

Polyvinylpyrrolidone (PVP), formerly a plasma expander, has continued to be inappropriately used in Taiwan for intravenous injection as a "blood tonic." Five cases of PVP storage disease with cutaneous involvement were studied. Two patients presented with cutaneous eruptions mimicking collagen vascular disease and chronic pigmented purpuric dermatosis. Two other cases were found incidentally: one was with a metastatic tumor and the other in a pemphigus lesion. The fifth case was seen in a blind skin biopsy specimen taken to exclude Niemann-Pick disease after hematologic examination of a bone marrow smear. The latter patient and the patient with a collagen vascularlike disease also had severe anemia and serious orthopedic and neurologic complications due to massive infiltration of PVP-containing cells in the bone marrow with destruction of the bone. Severe irreversible anemia due to PVP storage disease has not been reported before. Three patients admitted having a history of receiving intravenous injection of PVP. The samples obtained from two of them indeed contained 5% PVP as determined by chemical analysis. PVP storage disease can be diagnosed by its histopathologic features. The skin biopsy specimens all showed a variable number of characteristic blue-gray vacuolated cells around blood vessels and adnexal structures with positive tinctorial reactions to mucicarmine, colloidal iron, and alkaline Congo red and negative to periodic acid-Schiff (PAS) and alcian blue. The PVP storage cells were shown to be CD68+ macrophages. The presence of PVP in the skin induced little or no inflammatory reaction. Only the pelvic mass in one patient had a foreign body granuloma formation. Our study showed that systemic parenteral administration of PVP preparation could result in the accumulation of PVP storage cells in the skin, with or without clinical eruptions. The diagnosis of systemic PVP storage disease can be established by performing a skin biopsy for pathologic study. It is important for pathologists and clinicians to be aware of this iatrogenic storage disease to avoid misdiagnosis for hereditary storage disease, osteomyelitis, or signet-ring cell carcinoma. Serious hematologic and orthopedic complications can be caused by repeated massive intravenous injection of PVP. Therefore, PVP preparations should be strictly prohibited for systemic administration.

Adult↗
PubMed1997

Baculovirus gp64 gene expression: negative regulation by a minicistron.

Small upstream open reading frames (ORFs) or minicistrons located in the 5' leader of eukaryotic mRNAs have been shown to play a role in translational regulation of some eukaryotic genes, particularly mammalian proto-oncogenes. A survey of the baculovirus Autographa californica multicapsid nuclear polyhedrosis virus genome suggests that at least 10 transcripts from late genes contain potential minicistrons, and at least three of these minicistrons appear to be conserved in homologous genes of the related Orygia pseudotsugata MNPV. The position of the minicistron from one of these genes, gp64, is also conserved in gp64 genes from several baculoviruses, suggesting a potential regulatory function. To identify the potential role of the gp64 minicistron in regulating translation from gp64 late mRNAs, we generated a series of recombinant viruses containing the gp64 promoter and minicistron in combination with a chloramphenicol acetyltransferase reporter gene (cat) inserted into the polyhedrin locus. We first fused a cat reporter in frame with the minicistron coding region to demonstrate that the minicistron initiator ATG was in a context suitable for translational initiation. In subsequent experiments, a cat reporter was fused in frame to the downstream gp64 ORF, and various constructs containing point mutations that inactivated the minicistron were examined. Translational efficiency in the presence and absence of the minicistron was measured by quantitative analysis of gp64-cat RNA and the GP64-CAT protein. In the absence of a functional minicistron, translational efficiency from the downstream gp64-cat reporter ORF increased. Surprisingly, single-point mutations that inactivated the minicistron initiator ATG also resulted in utilization of an upstream in-frame ATG that is found within the minicistron coding region and that is in a poor translational initiation context. Double-point mutation constructs that inactivated both the minicistron initiator ATG and the upstream in-frame ATG also resulted in increased translational efficiency from the downstream gp64-cat ORF. Thus, the gp64 minicistron serves as a negative regulatory element that decreases translation of the gp64 ORF on late mRNAs.

Animals↗
PubMed1996

Interleukin 1 alpha and gamma-interferon induction of nitric oxide production from murine tumor-derived endothelial cells.

The role of nitric oxide (NO) in vascular function, host tumoricidal activity, and antiinflammatory effects is well documented. A number of cytokines induce NO from a variety of cell types. We have demonstrated in murine models that interleukin 1 alpha (IL-1 alpha) induces acute hemorrhagic necrosis, microvascular injury, and enhanced clonogenic tumor cell kill. Effects on the vasculature are observed only in tumor and not in normal tissues. Using methods established previously in our laboratory, murine tumor-derived and normal endothelial cells were cultured with IL-1 alpha, IFN-gamma, or IL-1 alpha/IFN-gamma at various doses with NO production quantitated through the measurement of nitrite by the Griess reaction. In tumor-derived endothelial cells, we demonstrated that neither cytokine alone was capable of inducing nitrite but that the combination of IL-1 alpha/IFN-gamma induced dose-dependent nitrite, with peak levels observed after 4 days incubation. When tumor-derived, normal yolk sac, mouse brain, or mouse aortic endothelial cells were treated with IL-1 alpha (100 units/ml)/IFN-gamma (10 units/ml), tumor-derived endothelial cells produced significantly more nitrite when compared to the normal endothelial cells. Nitrite production from IL-1 alpha/IFN-gamma was sensitive to the nitric oxide synthase inhibitors, NG-methyl-L-arginine or NG-nitro-L-arginine in a dose-dependent manner. In addition, dexamethasone significantly inhibited nitrite production from IL-1 alpha/IFN-gamma-treated, tumor-derived endothelial cells. These studies suggest that the antitumor activity of IL-1 alpha may be mediated through the production of NO from tumor-derived endothelial cells.

Animals↗
PubMed1995

Antitumor activity of interleukin-1 alpha and cisplatin in a murine model system.

BACKGROUND: Interleukin-1 alpha (IL-1 alpha) has potent antitumor activity either alone or combined with alkylating agents such as cisplatin and mitomycin C or porfiromycin. Cisplatin is an effective chemotherapeutic agent in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). In the murine SCCVII/SF squamous cell carcinoma tumor model, IL-1 alpha induced acute hemorrhagic necrosis and increased clonogenic cell kill. OBJECTIVE: To determine the efficacy of cisplatin and IL-1 alpha, singly and in combination, in the treatment of SCCHN. METHODS: Syngeneic C3H/HeN mice were treated with single-dose, concurrent, intraperitoneal injections of cisplatin and interleukin-1 alpha 14 days after subcutaneous tumor implantation and were monitored for delayed tumor regrowth. RESULTS: Cisplatin alone, but not IL-1 alpha, induced significant delayed tumor regrowth when compared with control. The combination of IL-1 alpha and cisplatin was even more effective in delaying tumor regrowth than cisplatin alone. Fractional tumor volume was significantly reduced in animals treated with the combination of cisplatin and IL-1 alpha compared with those treated with IL-1 alpha alone. CONCLUSIONS: Results of interleukin-1 alpha and cisplatin dose-response experiments reveal that the combination of low-dose cisplatin and interleukin-1 alpha is more effective than high-dose cisplatin alone. Our data suggest that cisplatin and IL-1 alpha may be efficacious in the treatment of SCCHN.

Animals↗
PubMed1995

Survey of the conjugated linoleic acid contents of dairy products.

The objective of this research was to determine the content of conjugated linoleic acid, an anticarcinogen, in dairy products. Fifteen cheeses, three fermented dairy products (other than cheeses), and four fluid milk products (two brands for each product) were included in the survey. Total lipids, fatty acids, protein, moisture, and titratable acidity were also measured to determine the relationship between the content of these constituents and conjugated linoleic acid content. The conjugated linoleic acid content of cheeses ranged from 3.59 to 7.96 mg/g of lipid. Blue, Brie, Edam, and Swiss cheeses had significantly higher conjugated linoleic acid content than the other cheeses. Sharp Cheddar cheeses tended to have higher conjugated linoleic acid content than the medium Cheddar cheeses, but the increase was not significant. The conjugated linoleic acid content of the other fermented dairy products ranged from 3.82 to 4.66 mg/g of lipid, and cultured buttermilk had the highest content. The conjugated linoleic acid contents of four fluid milks ranged from 3.38 to 6.39 mg/g of lipid and were not significantly different from one another. Multiple linear regressions of conjugated linoleic acid content and the total fatty acid content indicated a relationship between conjugated linoleic acid content and the content of precursors and intermediates of conjugated linoleic acid formation, including linoleic and oleic acids.

Animals↗
PubMed1994

Potentiation by interleukin 1 alpha of cisplatin and carboplatin antitumor activity: schedule-dependent and pharmacokinetic effects in the RIF-1 tumor model.

We have previously demonstrated that the cytokine interleukin 1 alpha (IL-1 alpha) significantly potentiates the antitumor activity of a variety of chemotherapeutic agents, including cisplatin (cDDP). In studies described here, we examined the potential of combining IL-1 alpha and the platinum analogue carboplatin (CBDCA) and compared the schedule-dependent and pharmacokinetic effects for IL-1 alpha combinations with cDDP and CBDCA. RIF-1 tumor-bearing mice (C3H/HeJ) received i.p. injections of varying doses of CBDCA, alone or concurrently with IL-1 alpha (48 or 480 micrograms/kg). Clonogenic cell kill and tumor regrowth delay were significantly increased when CBDCA was combined with IL-1 alpha, at both doses, compared to either CBDCA or IL-1 alpha alone (P < 0.001 and P < 0.01, respectively). Although pretreatment with IL-1 receptor antagonist blocked the acute tumor hemorrhagic response induced by IL-1 alpha alone, IL-1 receptor antagonist only partially blocked IL-1 alpha enhancement of CBDCA or cDDP-mediated tumor cell kill. The IL-1 alpha enhancement of CBDCA-mediated tumor cell kill was highly schedule dependent, with maximum antitumor activity observed when IL-1 alpha was administered 4-12 h before CBDCA. In contrast, administration of IL-1 alpha from 24 h before or as late as 6 h after cDDP resulted in the same antitumor activity as simultaneous administration of cDDP and IL-1 alpha. Tumor and normal tissue platinum content were significantly increased by IL-1 alpha in animals treated with CBDCA (P < 0.01) but not in those treated with cDDP. The observed differences between cDDP and CBDCA may be explained by their known differential rates of clearance and protein binding affinities and are compatible with an induced alteration in CBDCA pharmacokinetics.

Animals↗
PubMed1994

Isolation and identification of fresh tumor-derived endothelial cells from a murine RIF-1 fibrosarcoma.

Tumor vasculature is anatomically heterogeneous and distinct from the vasculature found in normal mature tissues. Examination of the differences between tumor and normal vasculature is critical to the future design of therapeutic modalities which either target tumor vasculature or potentially enable more efficient delivery of tumor cytotoxic agents. Such efforts to date have been hampered due to the inability to isolate live endothelial cells from solid tumors. We report here the isolation of fresh, noncultured endothelial cells from a C3H/HeJ RIF-1 murine fibrosarcoma through the use of fluorescence-activated cell sorting based on antibody staining for angiotensin-converting enzyme with further characterization by uptake and metabolism of acetylated low-density lipoprotein, factor VIII staining, and electron microscopy.

Animals↗
PubMed1993

Synergistic enhancement by interleukin-1 alpha of cisplatin-mediated antitumor activity in RIF-1 tumor-bearing C3H/HeJ mice.

Administration of interleukin-1 alpha (IL-1 alpha) plus certain cytotoxic drugs causes substantially greater clonogenic tumor-cell kill and tumor-regrowth delay than does treatment with either agent alone. IL-1 alpha itself has little effect on tumor growth despite its ability to induce acute hemorrhagic necrosis, restrict tumor blood flow, and cause microvascular injury in a variety of murine model systems. To investigate further IL-1 alpha's ability to enhance the antitumor activity of cytotoxic drugs, we initiated studies to examine the effect of IL-1 alpha on cisplatin (cDDP)-mediated cytotoxicity using the RIF-1 tumor system. The antitumor activity of IL-1 alpha and cDDP was quantitated through standard clonogenic tumor-cell survival assays, a tumor hemorrhagic necrosis assay and tumor-regrowth delay studies, with the interaction between IL-1 alpha and cDDP being analyzed through median dose-effect. In vitro, IL-1 alpha had no enhancing effect on the cDDP-mediated tumor-cell kill. For examination of the in vivo efficacy of this regimen, RIF-1 tumor-bearing C3H/HeJ mice (14 days postimplantation) were treated concurrently with single i.p. injections of IL-1 alpha and/or cDDP at various doses. The increased clonogenic tumor-cell kill obtained with IL-1 alpha/cDDP was dose-dependent, with significant enhancement by IL-1 alpha being observed (P < 0.001), even at the lowest doses tested (2 mg/kg and 6 micrograms/kg for cDDP and IL-1 alpha, respectively), but it did not correlate with an increase in tumor hemorrhage. Using median dose-effect analysis, this interaction was determined to be strongly synergistic. When treated animals were monitored for long-term antitumor effects, combinations with IL-1 alpha significantly increased the tumor-regrowth delay and decreased the fractional tumor volume (P < 0.001). These results demonstrate that IL-1 alpha synergistically enhances cDDP mediated in vivo antitumor activity and suggest that the combination of IL-1 alpha and cDDP may have potential therapeutic application in the design of effective treatment modalities for cancer.

Animals↗
PubMed1993

Glutathione concentration and distribution in cervical cancers and adjacent normal tissues.

Intracellular glutathione (GSH) has been shown to play an important role in modulating the cellular response to many cytotoxic agents, including radiation and chemotherapeutic drugs. In this study, individual glutathione levels from contiguous blocks of cervical cancer tissue were determined in order to investigate the intratumor GSH distribution and variation, as well as the difference between tumor and its normal counterpart. The GSH content of a squamous cell carcinoma of the cervix was twofold higher than its normal counterpart, but there was no obvious difference in a case with adenoid cystic carcinoma. The tumor margin adjacent to normal tissue has a higher GSH content than the tumor center in a large tumor. Although the intertumor variation in GSH is different in these two tumors, a common coefficient of variation, 26, is observed, which may be used to estimate the range of tumor GSH if it can only be determined by a biopsy.

Carcinoma, Adenoid Cystic↗
PubMed1992

Differential effect in vitro of tumor necrosis factor-alpha (TNF) on normal and virus-infected erythroid progenitors from Friend virus (FVA)-infected mice.

In vivo administration of tumor necrosis factor-alpha (TNF) suppresses both normal and Friend virus (FVA)-infected erythroid progenitor cells (CFU-E). To examine the mechanism of erythroid suppression by TNF, we examined TNF's direct effect on normal and virus-infected cells in vitro. Productively infected fibroblast cell lines, fresh acute virus-infected spleen cells, and virus-infected CFU-E were sensitive, whereas uninfected CFU-E were resistant to TNF cytotoxicity in vitro. When FVA-infected erythroblasts were depleted from the spleen cell population in vitro with antivirus antibodies, TNF suppression of the remaining (uninfected) cells was abrogated. In contrast, both normal and virus-infected macrophage progenitor cells and immature erythroid progenitor cells were equally sensitive to TNF cytotoxicity in vitro. Normal erythroblasts had significantly fewer TNF receptors than FVA-infected erythroblasts, which also were morphologically less mature. These results suggest that TNF can differentially suppress late-stage virus-infected erythroid progenitors in vitro.

Animals↗
PubMed1991

Acute hemorrhagic necrosis of tumors induced by interleukin-1 alpha: effects independent of tumor necrosis factor.

Tumor necrosis factor (TNF), a protein synthesized in response to the endotoxin bacterial lipopolysaccharide (LPS), is the classical mediator of acute hemorrhagic necrosis of tumors. We have demonstrated that interleukin-1 alpha (IL-1 alpha), with a spectrum of activities very similar to those of TNF, also causes acute hemorrhagic necrosis of tumors. Both TNF and IL-1 induce a cascade of events including the synthesis or release of each other. The present studies were thus undertaken to determine whether the hemorrhagic necrosis induced in tumors by IL-1 alpha is due to TNF. Kinetic parameters of IL-1 alpha-induced hemorrhage were similar to those observed with recombinant murine TNF-alpha (TNF-alpha) or LPS in RIF-1 fibrosarcomas in C3H/HeN (endotoxin-sensitive) mice. However, the amount of TNF found in the sera or tumors of animals treated with LPS was more than 20-fold higher than in mice treated with IL-1 alpha, and LPS induced similar degrees of hemorrhagic necrosis, which was measured by determining the packed volume of red blood cells by 59Fe labeling. A low but significantly hemorrhagic dose of IL-1 alpha induced no detectable TNF in tumors. Pretreatment with 250 micrograms of neutralizing antibody to TNF had no effect on IL-1 alpha-induced hemorrhage, whereas TNF-alpha- and LPS-induced hemorrhagic effects were significantly reduced. These results demonstrate an important antitumor activity of IL-1 alpha that appears to be independent of TNF.

Animals↗
PubMed1991

Pharmacokinetics of 2',3'-dideoxyadenosine in dogs.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddAdo) and 2'-3'-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination (approximately 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3-11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites. Concentrations exceeding the in vitro minimal viral inhibitory concentration (2.4 micrograms/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 micrograms/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapid in vivo conversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.

Administration, Oral↗