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Biomedical subjects

I J Forbes

Publications and source records attributed to I J Forbes.

At least 37 records · Page 2Linked to original sources
PubMed1989

Modification by vasoactive drugs of tumour destruction by photodynamic therapy with haematoporphyrin derivative.

Since the vascular endothelium is a primary site of damage after photodynamic therapy (PDT), it seemed likely that drugs which affect the vasculature may modify the outcome of PDT. Noradrenaline, propranolol, hydralazine and phenoxybenzamine inhibited photodynamic damage to tumours if these drugs were administered concurrently with HPD, 2 h before irradiation. This inhibition was associated with reduced uptake of HPD into tumours. There was no inhibition if irradiation was delayed until 24 h after administration of vasoactive drug, presumably because HPD uptake continued after the drugs had ceased to affect the vasculature. Verapamil enhanced photodynamic destruction of tumours when administered concurrently with HPD and the enhancement was associated with increased uptake of HPD into tumours. Verapamil neither increased uptake of HPD nor enhanced photodynamic destruction of cells in vitro. When verapamil was administered after irradiation, regrowth of tumours was inhibited. A similar effect was previously demonstrated with glucocorticoids. Other calcium channel blocking agents diltiazem and nifedipine had no effect on uptake of HPD or inhibition of regrowth of tumours after PDT. Inhibition of capillary or stromal ingrowth into tumours seems a plausible explanation of this effect of verapamil. This commonly used drug may be useful to enhance the efficacy of PDT.

Animals↗
PubMed1987

Auranofin increases the affinity of phorbol dibutyrate receptors in chronic lymphocytic leukemia cells (B cells).

Previous studies have shown that auranofin (AF), a lipophilic gold I complex, modulates metabolic events in leukocytes stimulated by phorbol esters, whose major cellular binding site is now known to be the Ca++/phospholipid-dependent protein kinase (protein kinase C). In these experiments we have investigated the effect of AF on the binding of phorbol dibutyrate (PDBu) to human chronic lymphocytic leukemia (CLL) B cells. AF enhanced binding of PDBu to its receptor in CLL cells by a) causing an increase in the affinity of PDBu receptors from Kd 20.3 nM to 7.3 nM, and b) enhancing translocation of PDBu receptors to the cell membrane. The increase in PDBu binding induced by AF in whole cells was only partially reversible by EGTA or the intracellular Ca++ antagonist TMB-8. Studies performed with quin-2-labeled cells showed that 100 microM AF caused a mean (+/- SD) rise in cytosolic Ca++ levels from 0.41 (0.12) to 0.85 (0.33) (n = 5). Thus the mechanism by which AF increases binding of PDBu to its receptor appears to be partially dependent on Ca++. These effects of AF occurred at cellular levels achieved in mononuclear cells during chrysotherapy of patients with rheumatoid arthritis.

Auranofin↗
PubMed1987

Calcium ionophore A23187 enhances human neutrophil superoxide release, stimulated by phorbol dibutyrate, by converting phorbol ester receptors from a low- to high-affinity state.

The calcium ionophore A23187 acted synergistically with phorbol dibutyrate (PDBu) to stimulate human neutrophil superoxide production. A23187 shortened the lag period and markedly increased the initial rate of neutrophil superoxide production induced by suboptimal concentrations of PDBu. 1 microM A23187 reduced the EC50 value for superoxide release from 56 to 8 nM PDBu. This effect of A23187 was correlated with enhanced binding of [3H]PDBu to its receptor and a reduction in the dissociation constant (Kd) from 27 to 10 nM, without altering the apparent total number of phorbol dibutyrate receptors. These actions of A23187 were abolished in the presence of EGTA or TMB-8, confirming a dependence on Ca2+.

Caenorhabditis elegans Proteins↗
PubMed1987

Pharmacological modulation of photodynamic therapy with hematoporphyrin derivative and light.

The interactions between photodynamic therapy (PDT) with hemotoporphyrin derivative (HPD) and treatment with cytotoxic drugs have been examined using both an in vitro tissue culture assay and an in vivo transplantable mouse tumor assay. Adriamycin (0.5-4.0 mg/kg) administered with HPD and at the time of irradiation potentiated the photodynamic effect, doubling the duration of tumor control. Adriamycin administered after PDT was not as effective. Methotrexate (0.2 mg/kg) also potentiated the tumor response to PDT. The other cytotoxic agents tested, cyclophosphamide, thiotepa, vincristine, and 5-fluorouracil, did not result in significant increases in tumor responses at the doses tested. In contrast to the effects observed in vivo, Adriamycin inhibited the photodynamic destruction of Raji or Lewis lung carcinoma cells in vitro, in part by reducing the uptake of HPD. Methotrexate had no effect on either the uptake of HPD or the efficacy of photodynamic destruction of Raji cells in vitro. The discrepancy between the in vitro and in vivo results implies that the interaction between PDT and other pharmacological agents cannot be assessed in vitro.

Animals↗
PubMed1986

Calcium ionophore A23187 primes human B-cells for activation by phorbol dibutyrate by converting receptors for phorbol dibutyrate from a low to high affinity state.

The calcium ionophore A23187 synergised with phorbol dibutyrate-induced activation of human chronic lymphatic leukaemia B-cells, as assessed by modulation of the membrane receptor for mouse erythrocytes. Thus A23187 (1 microM), which alone had no effect on expression of the receptor for mouse erythrocytes, reduced the EC50 and shortened the lag period for modulation of this receptor by phorbol dibutyrate. This action of A23187 was shown to be due to enhanced binding of [3H]phorbol dibutyrate to its receptor (phospholipid/Ca++ dependent protein kinase C) whose affinity was altered from a predominantly low affinity state (Kd 83 nM) to high affinity (Kd 9 nM). A23187 had no effect on the total number of phorbol dibutyrate receptors. EDTA abolished these actions of A23187.

B-Lymphocytes↗
PubMed1985

Photocytotoxicity in vivo of haematoporphyrin derivative components.

Phototoxicity of haematoporphyrin derivative (HPD) and some of its component porphyrins was assayed using Lewis Lung Carcinoma transplanted in C57BL mice. Skin photosensitivity was assessed by measuring percentage increase in footpad thickness after exposure to light. HPD and its aggregate fraction photosensitised the skin, was active in tumour destruction and caused fluorescence in the tumour while the non-aggregate fraction and pure haematoporphyrin were inactive, both in treatment of tumours and in sensitising the skin. The commercial product, Photofrin II was also photoactive and protoporphyrin was slightly active. It is concluded that the therapeutic activity of HPD is associated entirely with the aggregate fraction and compounds effective in tumour phototherapy also sensitise the skin.

Animals↗
PubMed1985

Potentiation of photodynamic therapy with haematoporphyrin derivatives by glucocorticoids.

The effect of glucocorticoids on tumour destruction by photodynamic therapy (PDT) with haematoporphyrin derivative (HPD) and light has been examined in a transplantable mouse tumour model. Administration of glucocorticoid after irradiation enhanced the effect of PDT on both Lewis lung carcinoma and B16 melanoma. Administration of methylprednisolone acetate in depot form concurrently with HPD inhibited the response to PDT while soluble hydrocortisone sodium succinate had no effect. Correctly timed administration of glucocorticoid may have a place in treatment of human tumours by PDT with HPD. Glucocorticoid did not reduce the temporary photosensitivity of the skin induced by HPD.

Animals↗
PubMed1984

A subclass of albumin recognized by inhibition of phosphatidylethanolamine-mediated agglutination of mouse erythrocytes.

Agglutination of mouse erythrocytes by non-choline phospholipids is inhibited by a factor in mammalian sera. The inhibitor cochromatographed with albumin on dye-agarose conjugates, was retained by an anti-albumin affinity column, was neutralized by anti-albumin antibody and found in a serum fraction in which only albumin could be detected. A variety of commercial preparations of albumin (fraction V, crystalline) did not inhibit. However, they acquired potent inhibitory activity when treated with low molecular weight thiols. The inhibitory activity of serum was increased 8-fold by treatment with dithiothreitol. Other proteins were not activated in this way. Inhibitory activity increased with average free sulphydryl content of treated albumin, up to six thiol groups per molecule. Alkylation of these sulphydryl groups did not diminish inhibitory activity. Thiols also induced polymerization of albumin. Inhibitory albumin in serum was largely monomeric. We propose that the inhibitor is a type of serum albumin which is lost or inactivated during preparation of commercial albumin, and which shares a structural feature, necessary for inhibition, with thiol-reduced albumin and the ligand on mouse erythrocytes.

Adult↗
PubMed1984

A phosphatidylethanolamine-containing complex on human B cells that mediates rosette formation with mouse erythrocytes.

The maturation-associated human B cell rosette receptor (MER) for mouse erythrocytes has been solubilized from B cells by mild trypsinization. It specifically agglutinates mouse red cells. Material with hemagglutinating activity partitioned into the lipid-soluble phase of a Folch partition of the trypsin extract was sensitive to phospholipase C and alkali, and on two-dimensional thin layer chromatography, it co-migrated principally with phosphatidylethanolamine (PE). Phosphatidylcholine, the major lipid present, was inactive. The relationship of phospholipid structure to hemagglutinating activity has been described. PE in the crude trypsin extract was associated with unidentified glycoprotein and albumin. Material containing hemagglutinating lipid bound to a wheat germ lectin-Sepharose column and was released by N-acetylglucosamine, indicating that the PE was complexed with glycoprotein. When the crude trypsin extract or eluate from the lectin column was extracted with aqueous phenol, hemagglutinin in the aqueous phase no longer bound to wheat germ lectin-Sepharose; however, albumin was greatly enriched, indicating that some of the PE exists in a complex with albumin. The molar ratio of PE to albumin was approximately 200:1. After delipidation, this albumin (in molar excess) inhibited hemagglutination by PE in the same way as a recently described subclass of serum albumin. Studies with phospholipase-treated B cells were also consistent with PE being the MER. We conclude that MER is PE, existing in a complex containing glycoprotein and a subclass of albumin. The capacity to form rosettes can be transferred to nonrosetting Raji B cells by the complex, but not pure PE, indicating that the proteins may be involved in orienting PE correctly for it to function as the MER.

Animals↗
PubMed1984

Mechanism of induction of mouse erythrocyte receptor switch in human B cells.

An early event in phorbol ester-induced maturation of chronic lymphocytic leukemic (CLL) B cells is a membrane change characterized by the inactivation of a mouse erythrocyte receptor (MER). This event, the MER-switch, is quantified by inhibition of rosette formation. By using [3H]phorbol dibutyrate ([3H]PDBu), both to stimulate MER-switch and assay binding of PDBu to CLL cells, it was shown that MER-switch was an irreversible, time-dependent event which occurred some time after maximal binding of [3H]PDBu to cells. Two classes of binding sites, one of high affinity (Kd 1 to 2 nM) at low frequency (1.5 to 5 X 10(4) sites per cell), and a lower affinity site (Kd 33 to 50 nM) of higher frequency (2 to 3.5 X 10(5) sites per cell), were detected. Binding of [3H]PDBu was inhibited by phorbol ester analogs that stimulated MER-switch, but not by inactive analogs. This, and the similarity in shapes of the binding and rosette inhibition curves over a range of concentrations, suggests that stimulation of MER-switch by phorbol esters is due to this specific binding. The phorbol ester receptor and MER are distinct because MER-ve T cells and MER-ve atypical B cells from a patient with CLL had both classes of PDBu receptor. Solubilized MER did not bind [3H]PDBu. Time-course studies, and the irreversibility of the switch, despite removal of most of the bound [3H]PDBu, indicate that inhibition of rosetting is not due to competitive or steric hindrance by phorbol esters. Equivalent activities of soluble MER were released from fresh and phorbol ester-treated CLL cells, indicating a rearrangement of MER, rather than a loss. A supernatant of phytohemagglutinin-stimulated human spleen cells also induced MER-switch in CLL lymphocytes, suggesting that a lymphokine may be a natural inducer of this event.

Animals↗
PubMed1983

Agglutination of mouse erythrocytes by binding of non-choline phospholipids to a 70 000-Dalton protein.

The structure of some phospholipids that cause agglutination of mouse erythrocytes has been studied. Haemagglutination is a property of non-choline-containing phospholipids; the phosphate group is essential and unsaturated fatty acids optimal. A protein of Mr 70 000 was isolated from mouse erythrocyte membranes which completely inhibited phospholipid-mediated erythrocyte agglutination. It is proposed that this protein is the phospholipid binding site on mouse erythrocytes and the ligand for the human B-lymphocyte receptor for mouse erythrocytes. Preliminary investigations suggest that a similar inhibitor of phospholipid-mediated agglutination is found in serum. Agglutination of mouse erythrocytes by phospholipid and specific inhibition by the 70 kDa membrane protein constitute a simple system for studying the interaction of phospholipid with protein.

Animals↗