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Biomedical subjects

P D Brown

Publications and source records attributed to P D Brown.

At least 19 recordsLinked to original sources
PubMed1996

Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94).

We examined the effects of the synthetic matrix metalloproteinase inhibitor batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent. Administration of batimastat (6 x 30 mg/kg i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung colonies following i.v. inoculation of cells. This implies an effect both on seeding efficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgical removal) significantly inhibited lung metastasis but had little effect on lymphatic metastasis. However, when treatment was initiated 2 days prior to surgery and continued until day 70, 100% of animals survived to day 120 when there was no evidence of metastatic disease. All control animals (n = 25) in two separate experiments died before day 100 with lymphatic, lung, and extrapulmonary metastases. Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular invasion, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing sustained tumor-free survival.

Animals↗
PubMed1996

[Survival after childhood cancer in Denmark 1943-1987. A population-based study].

Survival from cancer in childhood and adolescence was studied in 8312 children aged 0-19 years notified to the Danish Cancer Registry during 1947-1987. During the first period (1943-1972), five-year survival rates from all malignant neoplasms increased from 23% (1943-1952) to 33% (1963-1972). The greatest improvement was seen during the period 1973-87 when five-year survival rates reached 64% (1983-1987). Between 1973-1977 and 1983-1987, five-year survival rates increased from 32% to 62% for leukaemia, from 40 to 70% for acute lymphoblastic leukaemia, from 35 to 54% for non-Hodgkin's lymphoma, from 50 to 66% for central nervous system neoplasms and from 25 to 49% for bone tumours. An improvement in five-year survival rates for Wilms' tumour was seen between 1960 (19%) and 1980 (81%). Up to 1972, the five-year survival rate from germ-cell neoplasms was approximately 40%; among patients diagnosed in 1973-1987, 76% survived for five years. Survival was similar for boys and girls during the early period, but was significantly higher for girls subsequently. A marked effect of age at diagnosis was seen in the early registration period where survival rates for the age group 0-9 years was substantially lower compared to the age group 10-19 years. This inequality persisted only for children less than two years of age in the later period.

Adolescent↗
PubMed1996

A volume-activated anion conductance in insulin-secreting cells.

The whole-cell patch-clamp recording technique was used to measure volume-activated currents in K+-free solutions in RINm5F and HIT-T15 insulinoma cells and in dispersed rat islet cells. Cell swelling, induced by intracellular hypertonicity or extracellular hypotonicity, caused activation of an outwardly rectifying conductance which could be subsequently inactivated by hypertonic extracellular solutions. The conductance required adenosine 5'-triphosphate (ATP) in the pipette solution but was Ca2+ independent. Na+ and Cl- substitution studies suggested that the swelling-activated current is Cl- selective with a halide permeability sequence of Br > Cl > I. The conductance was reversibly inhibited by the anion channel inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Further evidence for a volume-activated anion conductance was provided by studies of volume regulation in insulin-secreting cells. When RINm5F cells were exposed to a hypotonic medium, the initial cell swelling was followed by a regulatory volume decrease (RVD). This RVD response was also inhibited by DIDS and by NPPB. These data therefore provide evidence for a volume-activated anion conductance in insulin-secreting cells which could be involved in the RVD following osmotic stress. A possible role for the conductance in hypotonically induced insulin release is also discussed.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Regulatory volume increase in rat lacrimal gland acinar cells.

The volume of acinar cells isolated from rat lacrimal glands was measured during hypertonic shock. Cells shrank in hypertonic solutions, but a regulatory volume increase (RVI) was only observed under certain conditions. In HEPES-buffered solutions at 37 degrees C, an RVI was observed. This was inhibited by 20 microM bumetanide, an inhibitor of Na(+)-K(+)-2Cl- cotransport. RVI did not occur in HEPES-buffered solutions at 20 degrees C suggesting that Na(+)-K(+)-2Cl- cotransport is inactive at this temperature. In HCO3- buffered solutions however, an RVI was observed at 20 degrees C. In these conditions, the RVI was inhibited by 500 microM 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (H2-DIDS) and 10 microM 5-(N-methyl-N-isobutyl)-amiloride (MIBA) indicating the involvement of Cl(-)-HCO3- exchange and Na(+) -H+ exchange respectively. RVI was also supported by a mixture of neutral amino acids, and by the nonmetabolizable amino acids 5 mM alpha-(methylamino)isobutyric acid (MeAIB) and 5 mM alpha-aminoisobutyric acid (AIB). These data suggest that the accumulation of amino acids, possibly by the system A Na(+)-coupled amino acid cotransporter, contributes to RVI in these cells. In conclusion, rat lacrimal gland acinar cells are capable of undergoing RVI following shrinkage by hypertonic shock.

Amino Acids↗
PubMed1995

Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models.

The effect of the matrix metalloproteinase inhibitor batimastat was evaluated in two human colorectal cancer metastasis models involving: (a) the liver-invasive tumor C170HM2 and (b) the lung-invasive tumor AP5LV, both of which have been shown to express the M(r) 72,000 type IV collagenase. Batimastat at concentrations between 0.01 and 3.0 micrograms/ml had no direct cytotoxic effects on the in vitro growth of the cell lines. In the liver-invasive tumor model, batimastat administered i.p. from day 10 to termination of the therapy (day 39) at 40 mg/kg reduced both the mean number of liver tumors (35% of vehicle-treated control; P < 0.05) and the cross-sectional area of the tumors (43% of vehicle-treated control; P < 0.05). In the lung-invasive tumor model, batimastat administered daily (40 mg/kg i.p.) significantly reduced tumor weight within the lung (72% of vehicle-treated control; P < 0.05) but did not significantly affect nodule number. In the latter model, in which the take rate was unaffected, tumor cells were introduced into the lateral tail vein, and lung localization may have been a physical phenomenon not involving invasion. In the former model, tumor cells were introduced directly into the peritoneal cavity, and from there the cells adhered to and invaded the liver capsule. Because the take rate is significantly reduced, it may be that the matrix metalloproteinases are involved in this process. Batimastat may be a therapeutic modality for the treatment of colorectal cancer metastasis.

Animals↗
PubMed1995

Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases.

BACKGROUND: The importance of matrix metalloproteinases in angiogenesis, tumor growth, and metastasis is well known. However, little is known about the role of matrix metalloproteinases in the formation of hemangiomas and about the possible therapeutic use of matrix metalloproteinase inhibitors in aggressive vascular tumors. PURPOSE: To study the role of matrix metalloproteinase in vascular tumors, we tested the antineoplastic activity of a synthetic inhibitor of matrix metalloproteinases, batimastat, on an experimental model of hemangioma, formed by murine endothelioma cells transformed by polyoma middle-T oncogene (eEnd.1). METHODS: The effect of batimastat was studied in vivo on the formation of hemorrhaging, cavernous hemangiomas by eEnd.1 endothelioma cells injected subcutaneously in nude mice and on the angiogenic response induced by an endothelioma cell supernatant embedded in a pellet of reconstituted basement membrane (Matrigel). The effect of batimastat was investigated in vitro on endothelial cell proliferation, motility, and invasion of a layer of Matrigel. RESULTS: Daily treatment with batimastat (30, 3, and 0.3 mg/kg at the site of eEnd.1 cell injection) inhibited tumor growth, with increased doubling time. The carboxamide derivative of batimastat, BB-374, a poor inhibitor of matrix metalloproteinase activity, was less active in reducing hemangioma growth. Histologic analysis of treated tumors indicated a reduction in the size of blood-filled spaces and in hemorrhage. Batimastat also inhibited the angiogenic response induced by cultured eEnd.1 endothelioma cell supernatant embedded in a pellet of Matrigel. Batimastat significantly inhibited endothelial cell invasion in vitro through a layer of Matrigel, but it showed no direct cytotoxic activity. CONCLUSIONS: Batimastat reduces in vivo growth of experimental hemangiomas, most probably by blocking endothelial cell recruitment by the transformed cells or by interfering with cell organization in vascular structures. IMPLICATIONS: These results confirm the importance of matrix metalloproteinase in endothelial cell recruitment that occurs in angiogenesis and in the formation of vascular tumors and suggest a therapeutic potential for synthetic matrix metalloproteinase inhibitors.

Animals↗
PubMed1995

Matrix metalloproteinase inhibitors: a novel class of anticancer agents.

Matrix metalloproteinase inhibitors represent a new therapeutic approach to the treatment of advanced cancer. These inhibitors block the activity of proteolytic enzymes, matrix metalloproteinases, used by tumor cells to break down and remodel tissue matrices during the process of metastatic spread. As such they were regarded initially as inhibitors of metastasis. However, recent studies have shown that these inhibitors can also act to inhibit tumor growth by (i) preventing local invasion and promoting stromal encapsulation and (ii) by inhibiting tumor neovascularization. Matrix metalloproteinase inhibitors therefore have the potential to halt tumor progression and it is possible to envision their use as a low toxicity complement to cytotoxic therapies. Batimastat (BB-94) is the first inhibitor of this class to enter clinical trial in cancer patients. In a phase I/II trial in patients with malignant ascites batimastat was well tolerated and there were preliminary signs of efficacy.

Animals↗
PubMed1995

Serotonin elevates intracellular Ca2+ in rat choroid plexus epithelial cells by acting on 5-HT2C receptors.

The effects of serotonin (5-HT) on intracellular calcium activity ([Ca2+]i) in epithelial cells from rat choroid plexuses were examined. Experiments were performed on isolated cells which had been maintained in primary culture. ([Ca2+]i) was measured using micro-spectrofluorimetric techniques and the fluorescent indicator Fura-2. 5-HT was found to increase [Ca2+]i in a dose dependent manner. The [Ca2+]i response was biphasic, with an initial peak of [Ca2+]i (due to release from intracellular stores), followed by an elevated plateau phase (the result of calcium influx). The effect of 1 microM 5-HT was inhibited by mesulergine and mianserin (50 nM), which are antagonists of the 5-HT2C receptor. Spiperone and ketanserin (200 nM), less specific 5-HT2 receptor blockers, caused only a slight reduction in the response to 1 microM 5-HT. The [Ca2+]i response decreased upon repeated challenges with 1 microM 5-HT, probably as a result of receptor desensitisation. Taken together, the data suggest that 5-HT acts at 5-HT2C receptors to increase [Ca2+]i in choroid plexus epithelial cells, both by liberating Ca2+ from intracellular stores and by activating a Ca2+ influx pathway.

Animals↗
PubMed1995

Matrix metalloproteinase inhibition: a review of anti-tumour activity.

BACKGROUND: Matrix metalloproteinases are a homologous family of proteolytic enzymes. Collectively, these proteinases are capable of degrading all components of the extracellular matrix, including proteolytically resistant fibrillar collagens. Extracellular matrices constitute the principal barrier to tumour growth and spread, and there is now experimental evidence that malignant tumours utilise matrix metalloproteinases to overcome this barrier. Inhibitors of matrix metalloproteinases may therefore be of therapeutic value in the treatment of metastatic disease. DESIGN: This review describes the activity of matrix metalloproteinases inhibitors (MMPIs), in experimental tumour models and in phase I/II clinical studies. RESULTS: Studies with MMPIs in vitro have shown that these agents are not cytotoxic but can inhibit the degradation of extracellular matrix by tumour cells. In experimental tumour models in vivo, MMPI treatment caused inhibition of tumour growth and metastatic spread in both rodent syngeneic and human xenograft models. MMPIs have also been shown to inhibit angiogenesis, a process essential for the rapid growth of most malignancies. CONCLUSIONS: MMPI therapy has the potential to arrest tumour growth and spread. As a non-cytotoxic 'tumourostatic' approach it may offer an ideal complement to surgery, radiotherapy and chemotherapy in the successful long-term treatment of metastatic disease.

Animals↗
PubMed1995

Evaluation of the polymerase chain reaction for early diagnosis of leptospirosis.

Early diagnosis of leptospirosis is important because severe leptospiral infection can run a fulminant course. The polymerase chain reaction (PCR) was evaluated for the detection of leptospires in clinical samples from patients with acute leptospiral infection. Blood and urine samples from 71 patients with leptospirosis were examined by PCR, culture or serology. Samples from 44 (62%) patients with the diagnosis of leptospirosis were positive by PCR as compared to 34 (48%) by culture. The presence of leptospires was demonstrated by PCR in 13 patients before the development of antibodies, as well as in two patients who were seronegative during their illness and at autopsy. Samples from 16 patients without leptospirosis were seronegative and culture negative, and also negative by PCR. We conclude that PCR is a rapid, sensitive and specific means of diagnosing leptospiral infection, especially during the first few days of the disease.

Acute Disease↗
PubMed1995

Intracellular pH modulates the activity of chloride channels in isolated lacrimal gland acinar cells.

The effects of intracellular pH (pHi) on Ca(2+)-activated Cl- currents in rat lacrimal gland acinar cells were examined. Cl- currents were recorded by conventional whole cell patch-clamp methods using K(+)-free and Na(+)-free solutions. pHi was varied by using electrode solutions with pH at 6.8, 7.3, or 7.8, and Ca2+ activity was buffered at 100 nM with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. Increasing pH from 6.8 to 7.8 was found to increase whole cell currents. The currents observed exhibited time-dependent activation at depolarizing potentials and time-dependent inactivation at hyperpolarizing potentials (pH 7.8). This behavior is characteristic of Ca(2+)-activated Cl- channels in lacrimal gland cells. The selectivity of the current was examined at pH 7.8 by removing Cl- from the bath solution. This maneuver caused a positive shift in the reversal potential, as expected for a Cl(-)-selective current. Thus increasing pHi appears to activate Ca(2+)-activated Cl- channels. The possibility that an increase in pHi may help sustain Cl- channel activity during secretory activity is discussed.

Acetylcholine↗
PubMed1994

Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice.

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.

Adenocarcinoma, Mucinous↗
PubMed1994

Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor.

The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.

Animals↗
PubMed1994

Immune globulin use at a multihospital medical center.

Use of i.v. immune globulin (IVIG) at four hospitals was audited to evaluate the need for therapeutic protocols and identify strategies for reducing drug expenditures. Charts and nursing notes for patients who received IVIG over a six-month period were reviewed retrospectively to obtain the following data: patient demographics, indication for IVIG use, product used, amount administered, and adverse reactions. Indications were categorized as to whether they are included in FDA-approved labeling, recognized in national guidelines, documented in published studies, or not documented. Expenditures were calculated from acquisition costs. At the first hospital (which offers oncology and other specialty services for adult patients), 71 patients received IVIG for 15 indications, with 89.5% of the orders for unlabeled uses. Of all grams reconstituted, 17.8% were wasted. The rate of documented adverse reactions was 11.3%. At the second, a pediatric hospital, 34 patients received IVIG for six indications, with 65% of the orders for unlabeled uses. Of all grams reconstituted, 13% were wasted. At the third hospital (which specializes in emergency trauma and critical care medicine), two patients received IVIG for a labeled indication. At the fourth (a maternity hospital), no patients received IVIG. Three of four hospitals used IVIG during a six-month audit period. In most instances, the drug was used for indications not included in FDA-approved labeling. Audit information may be useful in creating guidelines for appropriate use of IVIG.

Critical Care↗
PubMed1994

Ca(2+)-activated K+ channels are involved in regulatory volume decrease in acinar cells isolated from the rat lacrimal gland.

The volumes of acinar cells isolated from rat lacrimal gland were measured on computer by video-imaging. Cells were found to swell on exposure to hypotonic solutions; they subsequently exhibited a regulatory volume decrease (RVD). RVD was inhibited in the absence of extracellular Ca2+, and by the K+ channel blocker tetraethylammonium chloride (2 mM TEA+). The possible involvement of K+ channels in RVD was further investigated in cell-attached patches. Exposing the cells to a hypotonic solution activated channels with a conductance of 141 +/- 6 pS (n = 11). These channels were partially blocked by 0.5 mM TEA+, and channel activation was not observed in the absence of extracellular Ca2+. Experiments in the inside-out patch configuration demonstrated that the channels activated by hypotonic stress were "maxi" Ca(2+)-activated K+ channels. It is concluded that the opening of these channels plays an important role in RVD, by facilitating K+ loss from the cell.

Animals↗
PubMed1994

Evidence for two types of potassium current in rat choroid plexus epithelial cells.

The whole-cell patch-clamp technique was applied to rat choroid plexus epithelial cells. The resting membrane potential was -53 mV. The whole-cell conductance was mainly K+ selective, and the K+ current observed appeared to contain two distinct components. Depolarizing voltage pulses (more positive than 0 mV) evoked time-dependent outward currents which resembled delayed-rectifying K+ currents in other tissues. The current exhibited time-dependent activation and, at potentials more positive than 40 mV, slower time-dependent inactivation. The reversal potential measured by tail current analysis showed a shift of 43 mV for a tenfold increase in extracellular K+ concentration ([K+]o). The current was reduced by extracellular 5 mM Ba2+, 5 mM tetraethylammonium (TEA+), 5 mM Cs+ and 1 mM 4-aminopyridine (4-AP). In contrast, hyperpolarizing voltage pulses evoked time-independent, inward-rectifying currents. The reversal potential measured by voltage-ramp commands showed a shift of 42 mV for a tenfold increase in [K+]o. The chord conductance did not appear to increase with increasing [K+]o. The current was reduced by extracellular 5 mM Ba2+ and 0.5 mM Cs+, but not by 5 mM TEA+ or 1 mM 4-AP. These data suggest that two populations of K+ channel contribute to the conductance of choroid plexus epithelial cells.

Animals↗