Biomedical subjects
Publications and source records attributed to J L Ambrus.
In a patient undergoing radiation therapy for recurrent, metastatic breast cancer, a mixture of propoxyphene and acetaminophen (Darvocet) was given for intercurrent viral infection. Discontinuation of therapy with this medication coincided with appearance of pneumonitis, reminiscent of the steroid withdrawal--related radiation pneumonitis.
AET (Aminoethyl-iso-thiouronium) was applied topically on irradiated pig skin in different vehicles (emulsions and solutions) for testing a protective effect. A simple normal saline solution (200 mg/100 ml) proved to exert the best effect, both macroscopically and histologically. The solution was applied two hours and immediately before the irradiation which consisted of one 2000 rad fraction with a 20 MeV electron beam. A protective effect was noticed only in the superficial epithelial layers, the deeper radiobiological effect remained unaltered.
Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.
The red blood cell flexibility was studied in the blood of twenty patients with severe peripheral vascular disease and twenty matched controls. Patients exhibited significantly less red cell flexibility than controls. In both groups there was an inverse relationship between age and red cell flexibility. No correlation was found between red cell flexibility and sex or smoking history. Pentoxifylline, a xanthine derivative which inhibits phosphodiesterases and platelet aggregation, was found to increase red cell flexibility. This effect of the drug was greater on red cells with imparied flexibility than on normal cells. Various prostaglandins by contrast were found to decrease red cell flexibility, this could be compensated for by pentoxifylline. Forty patients with COAD were treated intravenously with PgE1. Significant inhibition of platelet aggregation and clinical improvement was noticed. It is suggested that combinations of PgE1 and pentoxifylline should be explored in clinical studies.
In vivo thrombolytic studies in stumptailed monkeys indicated that pentoxifylline potentiates thrombolysis induced by urokinase activated human plasmin. Pentoxifylline as well as prostaglandin E1 released plasminogen activators and activated the fibrinolysin system. From this point of view pentoxifylline and prostaglandin E1 synergized with each other. Pentoxifylline potentiated the thrombolytic effect of prostaglandin E1 in vivo.
It was suggested that the antitumor effect of the interferons is based in part on their ability to stimulate increased cAMP production. We have explored the interaction of human fibroblastic beta interferon (HFIF) with a cAMP decomposition inhibitory pyrimido-pyrimidine derivative, Mopidamole (RA-233) in cultures of neoplastic and normal cell lines. Mopidamole potentiated the growth inhibitory effect of HFIF in cultures of ES-1 malignant melanoma cells, LNCaP prostatic carcinoma cells, RT-4 transitional carcinoma cells, HT-29 colon adenocarcinoma cells and in diploid fibroblast cells.
Cultures of osteoblast-like cells were established from calvariae of Sprague-Dawley rats. Pentoxifylline increased cAMP levels and calcium uptake in these cultures. However, calcium uptake increased at lower levels than required to increase cAMP levels. Thus, it is likely that cAMP unrelated mechanisms are also involved in these phenomena.
In vitro deformability of red blood cells from SS-genotype patients in vasoocclusive crisis of sickle cell disease was significantly improved by the in vitro addition of the xanthine derivative pentoxifylline (Trental). Monkeys transfused with discarded sickle cell crisis blood showed aggregation of red cells and platelets on metal screens inserted into arterio-venous anastomoses. This phenomenon could be prevented by pretreatment of the animals with 24 mg/kg of pentoxifylline. The possible mechanisms of action are discussed.
The prostaglandin and leukotriene inhibitor sodium meclofenamate (SM) failed to influence radiation therapy induced regression of 6C3HED Gardner lymphosarcoma in C3H mice. Recurrence after radiation therapy, however, was reduced by treatment with SM. During these experiments, we observed that if a tumor was "cured" by radiation therapy, it required inoculation of a larger number of cells to establish a second tumor. Presumably, a certain degree of immunity has developed. On the other hand, if a second tumor was already established, less tumor cells were needed to establish a third tumor. This may be related to immuno-suppressor products of the second tumor. This effect could be partly inhibited by SM, suggesting that prostaglandins and leukotrienes may be involved in this phenomenon.
The interferon system has been implicated in the diagnosis and potential treatment of acquired immune deficiency syndrome (AIDS). In our study of AIDS patients we have identified the presence of circulating serum interferon inactivator(s). These interferon inactivators were not detected in AIDS prodrome patients or in patients with classical Kaposi's sarcoma. The evidence suggests that interferon inactivators may play a role in the clinical manifestation of AIDS.
The xanthine derivative, Trental (pentoxifylline) was found to inhibit several human leukemic and lymphoma cell lines in tissue cultures. Optimal concentrations were less inhibitory for a normal B-lymphocyte cell line then for the neoplastic cell lines. In fact, small concentrations stimulated DNA synthesis in the normal cell line. Trental and beta-interferon appeared to be additive synergists at certain dosages. Possible mechanisms are discussed.
Metastatic malignant melanomas from 16 patients, extracted with Triton X-100, were analyzed for plasminogen activator activity by azocaseinolysis . In 6 cases tumor explants were set up also in short-term organ culture, and the rate of plasminogen activator secretion into the culture medium was determined. Both the extractable activator content [8.66 +/- 7.8 "Committee on Thrombolytic Agents" (CTA) U/g tissue] and the activator secretion rates (0.90 +/- 1.6 CTA U/g/hr) were low in comparison with values for other human tumors. In addition to the activity, the type of plasminogen activator also was determined by immunoinhibition with goat antihuman urokinase antibody in the azocaseinolytic assay, as well as by sodium dodecyl sulfate (SDS) gel electrophoresis followed by zymography on fibrin-agar, in the presence and absence of antibody. On the average, 77% of the activator activity was of the urokinase type in the extracts, and 90% in the culture fluids. Immunoperoxidase reaction for the detection of urokinase showed this enzyme to be localized mainly in the cell membrane of the melanoma cells; stromal elements showed no specific staining. These results are of interest in view of the findings made recently by investigators in several laboratories that in all but one of the melanoma cell cultures derived from metastatic human tumors, only the vascular type ("tissue activator") was cell associated or was secreted into the culture medium. The possible reasons for this discrepancy are discussed.
Etiologic and pathologic factors in clinical osteoporosis are reviewed. Techniques were developed to determine total skeletal calcium content with in vivo neutron activation analysis and to induce osteoporosis (in about three months) with low calcium diet, corticosteroid or heparin treatment in experimental animals. Genetic influence was demonstrated: C3H/St (Ha) mice were more susceptible to osteoporosis by all three modalities than C57B1/6 (J) mice. Fluoride was ineffective in preventing osteoporosis induced by either of these three modalities. Heparin induced osteoporosis was prevented by conjugated estrogens, progestins or their combinations. Progestins were shown in other studies to inhibit estrogen induced metaplasia and neoplasia. Combining estrogens with progestin may result in an increased therapeutic index for the prevention of postmenopausal osteoporosis. Human and salmon calcitonin, Deca - Durabolin, an anabolic steroid, Mopidamole, a pyrimidopyrimidine derivative, Trental, a methylxanthine derivative, certain 2-thiophene carboxylic acid derivatives and imidazoquinazolines exhibited anti-osteoporotic effects.
Hypercalcemia and hypercalcemic crisis are common and often life threatening complications of neoplastic disease. Even moderately increased mobilization of skeletal calcium can result in significant osteoporosis. This in turn can give rise to pathologic fractures, often followed by pulmonary fat embolism and death. Bone pain is at times the first sign of neoplastic disease and the reason for seeking medical help.
Legionella pneumophilia Philadelphia 1 and Knoxville 1 were examined by in vitro hemagglutination and dermal hypersensitivity reactions in guinea pigs for the presence of the enterobacterial common antigen. No ECA was found and no cross reactivity was demonstrated between ECA and the proteinaceous cross reacting antigen.
We previously demonstrated the development of a cloned human T cell hybridoma that secretes B cell growth factor (BCGF) in the absence of demonstrable interleukin 2 or B cell differentiation factor. Sephadex gel filtration chromatography demonstrated the m.w. of this factor to be 18 to 20K. The present studies were performed to further characterize the biochemical properties of the molecule and to determine its target cell specificity. Temperature stability studies showed the monoclonal BCGF to be stable at 37 degrees C for 12 hr and at 70 degrees C for 15 min; however, most (93%) of the activity was lost after incubation at 70 degrees C for 30 min. Aliquots of hybridoma supernatant were exposed to buffer solutions with variable pH with no diminution in activity over a pH range of 4.0 to 10.0 BCGF activity was not affected by 2-mercaptoethanol, neuraminidase, or nucleic acid denaturing enzymes. In contrast, all activity was destroyed by 10 M urea, trypsin, and chymotrypsin. Chromatofocusing demonstrated the isoelectric point of BCGF to be 6.3 to 6.6. Finally, absorption experiments demonstrated that BCGF activity was absorbed by large, activated B cells. Mitogen-stimulated T cell blasts, small resting B cells, and CESS cells failed to absorb BCGF activity from the hybridoma supernatant. These and future studies with purified monoclonal human BCGF should enhance our understanding of its immunochemical properties and of its role in the immunoregulation of human B cell responses.
Four Cynomologous monkeys (Mecaca fascicularis) received 2000 Rad whole brain irradiation. One remained untreated and exhibited loss of hair, facial edema, brain edema and hydrocephalus. There was loss of alertness and motor activity. One was scheduled to be treated with phenobarbital, but died in 24 hours after irradiation. One animal received 2 mg/kg dexamethasone I.M. daily. It died two weeks after irradiation apparently due to treatment related infection. One animal received 20 mg/kg sodium meclofenamate (Meclomen) orally daily. This animal showed no brain edema and only minimal hydrocephalus, delayed and incomplete hair loss and no facial edema. Further studies of this treatment appear to be justified.
Immunoreactive PGE2 was determined in 11 surgically removed malignant tumors. When compared to adjacent non-malignant tissues PGE2 content was significantly higher in the neoplastic tissues. These findings support the view that PG may play a role in cell proliferation and/or vascular supply to tumor tissues. The hypothesis was also discussed that PGE2 may represent a tumor against host defense since it can decrease spontaneous and antibody dependent cytotoxicity. PGE2 may also play a role in tumor induced osteoporosis and hypercalcemia. If this hypothesis is correct PGE2 synthesis inhibitors may be employed as auxiliary antitumor agents.