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Biomedical subjects

M Sela

Publications and source records attributed to M Sela.

At least 109 records · Page 6Linked to original sources
PubMed1991

Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth.

The ERBB2 (also called HER2, neu, and c-erbB-2) gene product, which encodes a growth factor receptor, was implicated in the malignancy of human adenocarcinomas. An antibody directed to the rat oncogenic receptor has been previously shown to have an antitumor effect in model systems. In an attempt to extend this observation to the protooncogenic human receptor and also to understand the underlying mechanism, we generated a panel of monoclonal antibodies specific to the extracellular portion of the ERBB2 protein. The effects of the antibodies on tumor growth were compared with their cellular and biochemical actions in vitro. Surprisingly, opposing in vivo effects were observed: although some antibodies almost completely inhibited the growth in athymic mice of transfected murine fibroblasts that overexpress Erbb-2, other antibodies either accelerated tumor growth or resulted in intermediate responses. When tested on cultured human breast carcinoma cells or ERBB2 transfectants, the tumor-stimulatory antibody was found to induce significant elevation of tyrosine phosphorylation of the ERBB2 protein. In contrast, only partial correlation was observed between the capacity to restrict tumor growth and the effects of the antibodies on receptor degradation and cellular proliferation in vitro. This suggests that the antitumor antibodies affect both receptor function and host-tumor interactions. Our results may help establish experimental criteria for the selection of specific antibodies for use either alone or in conjunction with other molecules as pharmacological antitumor agents.

Animals↗
PubMed1991

Indirect immunotargeting of cis-Pt to human epidermoid carcinoma KB using the avidin-biotin system.

Cis-diamminedichloroplatinum (II) (cis-Pt) complexed to a carboxymethyl dextran-avidin conjugate was targeted to biotin-monoclonal antibody 108 (b-MAb 108). This MAb recognizes the extracellular domain of the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma (KB) cells over-expressing EGF-R. Cis-Pt-carboxymethyl-dextran-avidin (Pt-dex-Av) containing 60-90 M cis-Pt/M avidin was administered 24 hr following b-MAb108 containing 3-5 M biotin/M MAb. This treatment was potentially more effective in suppressing the growth of established KB tumor xenografts, or in inhibiting the development of lung metastases in nude mice, than free MAb 108, free drug or MAb 108 followed by drug. Replacing b-MAb 108 by unbiotinylated antibody or by b-MAb of a different specificity also yielded lower suppressive effects. The sequential administration of Pt-dex-Av following b-MAb was more effective than introduction of the Pt-dex-Av when already complexed to b-MAb 108. The results presented in this preliminary investigation suggest that Pt-dex-Av is specifically removed from the circulation by b-MAb 108 concentrated at the tumor site.

Animals↗
PubMed1991

Short latency vestibular evoked response to angular acceleration impulse in human beings.

Vestibular evoked response (VsEP) to acceleration stimuli were recorded in experimental animals and in human beings by scalp electrodes. The stimuli are angular acceleration impulses (up to 30,000 deg/sec2) transmitted to the skull by special devices. The short latency vestibular evoked response consisted of several waves during the first 10 msec. The first two waves (P1 and P2), which are the most consistent, have been shown in cats to originate from the vestibular nerve and nucleus, respectively. The middle latency response is believed to be of myogenic origin. It is hoped that the recording of VsEP in human beings will enable the localization of the site of lesion in vertiginous patients.

Adolescent↗
PubMed1990

The effect of anti-alpha-fetoprotein-adriamycin conjugate on a human hepatoma.

Conjugates between chemotherapeutic agents and antibodies, linked by a dextran bridge, were previously shown to be effective in suppression of hepatoma growth in vitro and in vivo. However, scaling up of production of such conjugates may lead to a high degree of variation in molar ratios of drug to antibody in different batches. In this study, an alternative link between drug and antibody was evaluated. A conjugate between adriamycin and murine IgGI monoclonal antibodies to human alpha-fetoprotein was prepared using a polyglutamic-acid bridge. The simple and reproducible method of linking adriamycin to a specific site on the antibody enabled the binding of the drug to alpha-fetoprotein with a high yield (63% to 68%); the molar ratio of drug/antibody was in the range of 110:1 to 120:1. The conjugate retained its capacity to bind to purified alpha-fetoprotein. Incorporation of [3H]-thymidine or [3H]-leucine into hepatoma cells, which express alpha-fetoprotein, was inhibited by the conjugate, compared with unconjugated antibody. Furthermore, 90% of this pharmacological activity was preserved, compared with free adriamycin. In vitro, the inhibitory activity of the polyglutamic acid conjugate was higher than that of a conjugate in which dextran was used as the linker between drug and antibody. In vivo, both conjugates were equally effective in suppression of hepatoma growth transplanted subcutaneously in athymic mice. However, this effect lasted only during the treatment period of 2 to 3 wk. Six days after discontinuation of therapy, reacceleration of tumor growth was observed regardless of the conjugate used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Vestibular evoked potentials with short and middle latencies recorded in humans.

Following success in recording short latency vestibular evoked potentials in experimental animals, we have succeeded in our attempts to record such potentials in human subjects. The stimuli were repetitive, short steps of high intensity angular acceleration (10,000 degrees/sec2) with short rise times which would synchronously activate many neurons of the vestibular pathway. Stringent control procedures ensured that the recorded activity was not an artefact. Short latency vestibular evoked potentials were recorded in 10 normal subjects with peak latencies of 3.5, 6.0 and 8.4 msec and amplitudes of 0.5 microV. Middle latency potentials were also recorded with latencies of 8.8, 18.8 and 26.8 msec and amplitudes of 15 microV. These responses were absent in a cadaver and in patients with bilateral dead labyrinths. In normal subjects, these vestibular evoked potentials were not affected by white noise. In conclusion, short and middle latency vestibular evoked potentials were recorded in normal human subjects.

Adolescent↗
PubMed1989

[Clinical trial of copolymer 1 in multiple sclerosis].

A synthetic copolymer of amino acids, copolymer 1 (Cop 1), proved to be very effective in suppressing experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). It is 1 of a series of synthetic amino acid copolymers which simulate the basic protein constituent of the myelin sheath and the autoantigen responsible for induction of EAE. It cannot induce EAE but it does suppress it in a variety of animals. The immunological cross-reaction between Cop 1 and the basic protein is the basis for this suppressive activity. In view of the resemblance between EAE and MS, clinical trials with Cop 1 in MS were started. The first preliminary clinical trial was at this hospital and involved 4 patients with severe MS. A double-blind, randomized placebo-controlled pilot trial was carried on for 2 years in 50 patients with the exacerbating-remitting form of MS but with a Kurtzke Disability Status Scale rating of no more than 6. There were statistically significant differences in the number of patients with exacerbations in the placebo group, 23, as compared to only 16 in the Cop 1-treated group. As to exacerbations per patient, the 2-year averages were 2.7 and 0.6, respectively. Side-effects of Cop 1 were minimal. These results suggest that Cop 1 may be beneficial when given early in the exacerbating-remitting form of MS. Further trials, necessary to establish its efficacy in MS, are being run at the Albert Einstein College of Medicine in NY.

Amino Acids↗
PubMed1989

A mouth splint for severe burns of the head and neck.

An individual mouth splint device that applies continuous or intermittent pressure to stretch commissures and fibrotic muscles in patients treated for microstomia resulting from facial and neck burns is presented. After an individual lip tray is prepared, the method uses the impression and cast of the region of the lips to construct a pink acrylic resin splint. By using the device, split horizontally and activated with a Hyrx screw, an opening of 14 mm can be obtained within 2 weeks. The device is recommended as being easily constructed, inexpensive, almost painlessly inserted, and progressively activated.

Burns↗
PubMed1989

Inhibition of human tumor growth in nude mice by a conjugate of doxorubicin with monoclonal antibodies to epidermal growth factor receptor.

Monoclonal antibodies that recognize the extracellular domain of the epidermal growth factor receptor (mAb108) were conjugated with doxorubicin through a dextran bridge. Several antibody-drug conjugates, containing different amounts of doxorubicin, retained binding capacity to human epidermoid carcinoma (KB) cells overexpressing epidermal growth factor receptors. Slight decrease in drug cytotoxicity was seen in in vitro tests, as determined either by inhibition of thymidine incorporation into cells or by reduction in number and size of KB-cell colonies. Yet, when tested in vivo against KB tumor xenografted into nude mice, the anti-epidermal growth factor-receptor drug conjugates with high drug-substitution levels were significantly more effective than free doxorubicin, antibody alone, mixture of dextran-doxorubicin and antibody, or drug conjugated with irrelevant antibody. When the labile covalent bonds linking antibody to dextran bridge were stabilized by reduction, the therapeutic efficacy of the conjugate was markedly decreased. These results show that antibodies against the extracellular domain of the epidermal growth factor can deliver doxorubicin specifically and efficiently to tumor sites that express high receptor levels exerting a specific antitumor effect.

Animals↗
PubMed1989

Bilateral anophthalmia and unilateral microphthalmia in two siblings.

A family pedigree consisting of four uneventful pregnancies and deliveries is described. The 2nd sibling suffered from bilateral anophthalmia while the 4th presented a unilateral microphthalmia. Although the microphthalmia was originally interpreted as a possible manifestation of the same genetic trait expressed as bilateral anophthalmia in the elder sister, careful ophthalmic examination unveiled the real cause. A central corneal scar along with cataractous lens and a relatively clear peripheral cornea observed in the microphthalmic eye were compatible with an in utero perforation of the globe. Indeed, we believe that the perforation occurred at the time of the amniocentesis performed during midtrimester of this pregnancy.

Amniocentesis↗
PubMed1989

Prosthetic rehabilitation of mandibulectomy and glossectomy patients.

The prosthodontic prognosis in patients with lateral discontinuity defects of the mandible is dependent on a number of complex factors. In some patients only esthetics can be improved, whereas in others mastication and speech improvement can be achieved. Two patients who had undergone the same surgical interventions but presented with different problems are described. The first patient had difficulty with mastication and mandibular movements, which was resolved by building a ramp on a maxillary prosthesis. The second patient had severe speech and swallowing problems, which were corrected with an acrylic, hollow speech prosthesis. In both patients the end result was satisfactory.

Adult↗
PubMed1989

Suppression of experimental allergic encephalomyelitis by COP1--relevance to multiple sclerosis.

The evidence in this presentation clearly indicates that in the case of the model disease EAE, desensitization procedures are effective in suppressing the symptoms of the disease and in providing protection against it. The antigens used in our studies are all synthetic materials immunologically relevant to the myelin encephalitogenic protein, but not encephalitogenic themselves. The most effective of these materials is a random basic copolymer of alanine, glutamic acid, lysine and tyrosine, denoted COP 1. The finding that the suppressive polymers show immunological cross-reactivity with the encephalitogenic protein provides a logical basis for the explanation of their suppressive activity in terms of an immunological desensitization mechanism. Our studies suggest that the effectiveness of COP 1 in preventing EAE results from the production of antigen-suppressor T cells, and/or from blocking MBP-specific effector T cells. The results of the clinical trial presented here show demonstrable improvement in the COP 1-treated patients as compared with the placebo subjects, particularly for those patients with less severe MS at the start of the treatment. Thus, although the evidence supporting the antigenic role of MBP in MS is not strong, COP 1, a synthetic polypeptide simulating some of the properties of MBP, appears to be effective in altering the course of MS and is of potential value as a modality for the treatment of this disease.

Animals↗
PubMed1989

Metastatic maxillary sinus melanoma treated by local excision and brachytherapy.

Malignant melanoma has traditionally been considered a radioresistant tumor. A rare case of metastatic malignant melanoma into the nose and maxillary sinus is presented. Local control was achieved by a combination of local excision and teleradio and brachytherapy. The response of melanomas to radiation treatment is discussed in light of the recent literature.

Aged↗
PubMed1988

Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice.

Iodine-125-labeled monoclonal antibody 108.4 (108.4 mAb), raised against the extracellular domain of the epidermal growth factor (EGF) receptor, was shown to visualize sc xenografts of human oral epidermoid carcinoma (KB) cells in nude mice. In vitro, although EGF caused an increase in the number of KB cell colonies (150% at a concentration of 160 mM), the anti-EGF receptor antibodies reduced clone formation. At a concentration at which EGF caused a 50% increase in colony number, the addition of a 100-fold molar excess of 108.4 mAb resulted in a decrease in the number of cell colonies to 20% of the original value. Therefore, the effect of antibody on the KB tumor was studied in vivo in three different modes of tumor transplantation. Antitumor activity was demonstrated first by retardation (versus controls) of the growth of tumor cells as sc xenografts (P greater than .017), then by prolongation of the life span of animals with the ip form of the tumor (P less than .001), and finally on an experimental lung metastasis by a reduction in the number and size of tumors (P less than .05). When the anti-EGF receptor antibodies were added together with cisplatin, the antitumor effect was greatly enhanced, suggesting that the toxic activity of these agents is synergistic (P less than .007). The antitumor effect persisted when animals were treated with the F(ab)'2 fragment of the antibody, although it was less efficient. The Fab fragment of the antibody, whose ability to bind to the cell-associated receptor was completely conserved, did not affect the growth of the tumor. The activity manifested by the F(ab)'2 fragment of the anti-EGF receptor antibodies suggested that the antitumor effect was not due to immune mechanisms requiring the Fc portion of the antibody.

Animals↗