The avian c-fps and mammalian c-fes proto-oncogenes are cognate cellular sequences. Antiserum raised against the P140 ga,-S transforming protein of Fujinami avian sarcoma virus specifically recognized a 92,000-Mr protein in human and mouse hematopoietic cells which was closely related in structure to Snyder-Theilen feline sarcoma virus P87gOg-f's. This polypeptide was apparently the product of the human c-fes gene and was therefore designated p92c-fes. Human p92c-fes was associated with a tyrosine-specific protein kinase activity in vitro and was capable of both autophosphorylation and phosphorylation of enolase as an exogenous protein substrate. The synthesis of human and mouse p92c-fe was largely, though not entirely, confined to myeloid cells. p92c-fes was expressed to relatively high levels in a multipotential murine myeloid cell line, in more mature human and mouse granulocyte-macrophage progenitors, and in differentiated macrophagelike cells as well as in the mononuclear fraction of normal and leukemic human peripheral blood. p92cfes was not found in erythroid cells, with the exception of a human erythroleukemia line which retains the capacity to differentiate into macrophagelike cells. These results suggest a normal role for the p92c-fes tyrosine kinase in hematopoiesis, particularly in granulocyte-macrophage differentiation. In addition, a distinct 94,000Mr polypeptide, antigenically related to p92c-fes, was identified in a number of hematopoietic and nonhematopoietic human and mouse cells and was also found to be associated with a tyrosine-specific protein kinase activity.
Summary Plasma lipoproteins, such as low-density lipoprotein (LDL), have been proposed to enhance the delivery of hydrophobic photosensitisers to malignant tissue since tumour cells have been shown to have increased numbers of LDL receptors. We have investigated the role of this receptor in the cellular accumulation of the photosensitiser benzoporphyrin derivative (BPD). We observed that: (1) [`4C]BPD-LDL accumulation by LDL receptor-negative fibroblast cell lines was insignificant compared with normal cell lines; (2) there was no evidence that BPD dissociated from LDL during incubation with the cells; and (3) chemical acetylation of LDL markedly decreased the uptake of ['4C]BPD-LDL. We conclude, therefore, that virtually all of the photosensitiser accumulated by the cells was due to specific binding and internalisation via the LDL receptor. Subsequent in vivo studies in M-1 (methylcholanthrene-induced rhabdomyosarcoma) tumour-bearing DBA/2J mice showed that tumour accumulation of BPD associated with native LDL was significantly (P<0.01) enhanced over that of acetyl-LDL-associated BPD. These results indicate that the LDL receptor is responsible for the accumulation of LDL-associated BPD both in vitro and in vivo. Thus, utilisation of this delivery system may provide for improvements in photodynamic therapy in clinical practice.
Summary The in vivo characteristics of four analogues of benzoporphyrin derivative (BPD) (Brasseur et al., 1988; KreimerBirnbaum, 1989; Morgan et al., 1987a,b). Undoubtedly, the knowledge of these characteristics could help in selecting and/or designing photosensitisers for PDT. It appears likely, however, that no photosensitiser will have all of the desirable properties since no doubt, efficacious PDT is dependent on a large number of variables.We have been working with a chlorin-like photosensitiser, benzoporphyrin derivative (BPD), which is composed of four structural analogues following synthesis. All four analogues have an identical reduced tetrapyrrol porphyrin ring. They differ in two regards; the position of a cyclohexadiene ring which is fused at either ring A or B of the porphyrin, or in the presence of two acidic groups, or one acid and one ester group located at positions C and D of the porphyrins. In vitro characteristics of these analogues have been reported earlier (Richter et al., 1990a). Monoacid analogues were found to be more efficient photosensitisers than the diacids. Of the two monoacids, monoacid ring B (BPD-MB) was found to be slightly more soluble than the ring A analogue (BPD-MA) and preliminary in vivo work indicated that this could be a problem in obtaining reliable data because of the possible presence of aggregates in formulated materials. Therefore our studies on in vivo photosensitisation with BPD have focused largely on BPD-MA. The results are reported in this paper. We also report the results of limited studies carried out with other BPD analogues, undertaken in order to identify special characteristics which make a molecule of a photosensitiser efficient in in vivo PDT. Materials and methodsSynthesis of BPD analogues BPD was synthesised as described earlier . The length of hydrolysis of the dimethylester of A-ring or B-ring isomers with 25% hydrochloric acid dictates the final ratio between mono and diacids formed, longer hydrolysis leading to more complete conversion to the diacid form. The separation of the diacids from the monoacid analogues was carried out using column chromatography on silica gel as described earlier (Richter et al., 1990b). The following analogues were obtained: BPD-monoacid, ring A (BPD-MA), and ring B (BPD-MB), and BPD diacid, ring A (BPD-DA) and ring B (BPD-DB).All four BPD analogues were maintained in dimethyl sulfoxide (DMSO) at a concentration of 8 mg ml-'. Immediately before injection into the animals they were diluted in phosphate buffered saline (PBS). The injected solution contained no more than 10% DMSO.Tritiated BPD analogues Batches of BPD-MA, -MB and -DA were tritiated by NEN (Boston, Mass.) according to the procedure described earlier (Richter et al., 1990b). Two batches of BPD-MA were labelled and the specific activities were 5.9 mCi mg-' (1st batch) and 5.46 mCi mg-' (2nd batch). Specific activities of BPD-MB and BPD-DA were 9.2 mCi mg-' and 6.57 mCi mg-', respectively. The labelled compounds were tested for purity and photosensitising...
Benzoporphyrin derivative (BPD) has been demonstrated to be a new potent photosensitizer for photodynamic therapy (PDT). Although most of the work on BPD has been focused on its potential applications for cancer treatment, BPD may have potential clinical uses in the treatment of atherosclerosis. The purpose of this study was to determine in vitro and in vivo uptake of BPD into atherosclerotic plaque. Samples of atherosclerotic human femoral and popliteal arteries were incubated with BPD-monoacid, ring A (BPD-MA) for 1 h in the following concentrations: 1, 5, 10, 20, 30 and 40 micrograms/mL. Fluorescence from all samples was determined by chemical extraction with a spectrofluorometer. The tissue concentration for human arteries was 0.37 +/- 0.03, 2.78 +/- 1.5, 3.6 +/- 1.91, 7.15 +/- 2.36, 8.06 +/- 3.09 and 14.6 +/- 4.81 micrograms/g, respectively. In addition, three miniswine were rendered atherosclerotic and given BPD 2.0 mg/kg intravenously. The concentration of BPD-MA in miniswine aorta was 93-190 ng/g and the plaque/normal ratio was 1.7-3.5. For miniswine iliac arteries, the [BPD-MA] was 60-178 ng/g and the plaque/normal ratio was 1.1-3.3. Normal miniswine carotid artery contained 54 ng/g. This study showed that BPD-MA was taken up in atherosclerotic vessels both in vitro and in vivo and may have potential for PDT of atherosclerosis.
The term "photoimmunotherapy" describes an anti-cancer treatment that combines the phototoxic effects of chemical such as hematoporphyrin and the target-seeking ability of antibodies. Hematoporphyrin was chemically coupled to monoclonal antibodies directed to the DBA/2J myosarcoma M-1. Administration of anti-M-1-hematoporphyrin conjugates i.v. to M-1 tumor-bearing animals followed by exposure to incandescent light resulted in suppression of M-1 growth. The time interval between injection and light exposure was an important parameter in terms of tumor suppression. Tumor-bearing animals maintained in the dark for 96 to 196 hr after hematoporphyrin-antibody injection followed by 4-hr light exposure demonstrated significantly lower tumor incidence and longer latency periods, in comparison to conjugate-treated animals instantly exposed to light. The growth inhibiting properties of the conjugate appeared to be M-1-specific; it had no effect on the growth of a C57BL/6J lymphoma EL4. In addition, conjugates made with a nonspecific monoclonal antibody did not have any specific anti-tumor effect on M-1 growth. Treatment with equivalent doses of hematoporphyrin or antibody had no significant inhibiting effect on tumor growth. Clearly, the homing ability of the specific monoclonal antibody-hematoporphyrin conjugate was essential for effective drug delivery and inhibition of tumor growth.
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