Effect of bacterial purified antigenic fractions on natural defence mechanisms

The in vitro ability of bacterial purified antigenic fractions to interfere with the immune system has been investigated on human mononuclear cells from peripheral blood. Exposure of purified monocytes to the drug at concentrations from 1 to 1000 micrograms/ml, for different periods from 0 to 18 h, significantly increased cell-mediated cytotoxicity against TU5 target cells. Moreover, monocytes exposed for 1 to 18 h to drug concentrations from 0.1 to 1000 micrograms/ml released significant amounts of tumor necrosis factor alpha in a dose-dependent manner in the culture supernatants. The drug was also tested on natural killer (NK) cell activity; mononuclear cells exposed to antigenic fractions for different periods showed a significant increase of NK cytotoxic activity against K562 target cells after 3 and 6, but not 0 and 18 h. Active concentrations were from 1 to 100 micrograms/ml, higher and lower doses being ineffective. Bacterial purified antigenic fractions thus have some ability to interfere in vitro with mechanisms of cytolysis mediated by cells and soluble factors.     

The use of bone scan to evaluate total hip prostheses. A preliminary study

The authors conducted a clinical and radiographic study on a group of 43 patients with hip arthroprostheses selected from the three-year period from 1984 to 1987, characterized by no immediate postoperative complications, no positional defects on X-ray examination, and with a Renther test greater than 1. Prostheses were cemented, cementless and combined. Scintigraphy was evaluated for areas of subdivision in the proximal end of the femur and acetabulum, making a semi-quantitative comparison of the intensity of captation of each area with that of the skull and sacroiliac synchondrosis. The authors emphasize that this procedure is both reliable and easy for the early determination (pre-clinical and pre-radiographic) of any complications. A scintigraphic examination of the single areas was also capable of revealing the site and entity of prosthetic bone-to-implant interactions. According to the results reported, PCA prostheses seem to be characterized by better biocompatibility.     

The immunomodulatory activity of the plant proteins Momordica charantia inhibitor and pokeweed antiviral protein

The immunological activity of Momordica Charantia inhibitor (MCI) and of Pokeweed antiviral protein (PAP-S), 30,000 daltons plant proteins possessing close similarity to Ricin A chain as inhibitor of protein synthesis, was investigated in mice. In vivo, single nontoxic injections of microgram amount of these substances delayed H2-incompatible skin allograft rejection, splenocyte responsiveness to ConA and PHA, but not to LPS, and abrogated the PFC response to a T-dependent (SRBC) antigen while totally sparing that to a T-independent (S III) stimulus. Injection of these substances could also reduce NK cell activity while increasing macrophage-mediated spontaneous cytotoxicity. In vitro, MCI and PAP-S at non-cytotoxic concentrations inhibited lymphoid cell responsiveness to PHA and ConA, but not to LPS, and markedly enhanced macrophage-dependent cytotoxicity.     

Excitatory amino acids mediate responses elicited in vitro by stimulation of cortical afferents to reticularis thalami neurons of the rat

The effects of the excitatory amino acids on the nucleus reticularis thalami were examined by intracellular recordings from rat thalamic slices. Non-N-methyl-D-aspartate receptor agonists and glutamate induced a membrane depolarization and a reduction in input resistance, while N-methyl-D-aspartate and aspartate induced a prolonged discharge, which in some neurons took the form of a burst firing associated with an apparent increase in membrane input resistance. Both the N-methyl-D-aspartate and the aspartate effects were blocked by D-2-amino-5-phosphonovalerate, while the effects of glutamate, kainate and quisqualate were not. The excitatory postsynaptic potential evoked by corticothalamic fiber stimulation shows two components: an early, short-lasting, 2-amino-5-phosphonovalerate-insensitive portion, and a late, 2-amino-5-phosphonovalerate-sensitive decay phase. It is suggested that glutamate acts in nucleus reticularis thalami cells preferentially on the non-N-methyl-D-aspartate receptors, while aspartate shows an N-methyl-D-aspartate-like effect. The two excitatory amino acids glutamate and aspartate play a determinant role in the modulation of thalamic activity driven by corticothalamic projection.     

A characterization of the activity of α-1,3,5-triglycidyl-s-triazinetrione,a novel antineoplastic compound

Summary To extend initial results on the antineoplastic activity of -1,3,5-triglycidyl-s-triazinetrione (TGT, NSC 296934), a novel triepoxidic derivative, this compound was tested in a series of murine transplantable tumors. Repeated daily treatments with well-tolerated systemic doses of this chemical produced substantial retardation in tumor growth and significant prolongation of survival in the line 16 mammary, M5067 ovarian, and Madison 109 lung carcinomas and in mFS6 fibrosarcoma. Very marked activity was also seen in the P815 mastocytoma, B16 melanoma, line 38 colon carcinoma, and an intracerebrally transplanted ependymoblastoma, with high proportions of cures after one or two injections in IP transplanted SL2 lymphoma and line 26 colon carcinoma. It is concluded that the high level of antineoplastic effectiveness and the wide spectrum of TGT activity together with its novel structural characteristics could be of clinical significance.     

Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat

Summary A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P<0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was 12% lower than that measured in age-matched control rats (P<0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P<0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P<0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.     

Antigenic changes of L5178Y lymphoma after treatment with 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide in vivo.

Immunologic alteration of the L5178Y lymphoma was obtained in vivo after treatment with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DIC). A single dose of 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) "CURED" MICE CHALLENGED WITH L5178Y cells that had been treated with DIC (L5178Y/DIC) for four transplant generations; BCNU did not cure mice bearing the parent tumor. The L5178Y/DIC, treated in vivo for five transplant generations, id not grow in syngeneic mice. L5178Y/OIC cell growth and incidences of death were similar to those of parent cells when inoculated into heavily immunosuppressed mice. Adoptive transfer of lymphocytes from spleens of mice sensitized to the drug-altered tumor specifically protected immunosuppressed mice bearing the L5178Y/DIC tumor. Little protection was afforded by lymphocytes immune to the parent L5178Y tumor, whereas nonimmune lymphocytes or lymphocytes immune against unrelated tumors were completely ineffective. Anti-L5178Y/DIC lymphocytes did not cure mice challenged with the parent L5178Y tumor. Irradiated (400 R) mice previously sensitized to L5178Y/DIC cells rejected 10(2)-10(7) inocula of L5178Y/DIC cells and died when the parent L5178Y was used for challenge. It was concluded that antigeni( alterations of L5178Y cells occurred in (BALB/ctcr X DBA/2Cr)F1 mice after treatment with DIC in vivo.