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Biomedical subjects

F Lacour

Publications and source records attributed to F Lacour.

At least 37 records · Page 2Linked to original sources
PubMed1985

A phase I clinical tolerance study of polyadenylic-polyuridylic acid in cancer patients.

Polyadenylic-polyuridylic acid [poly(A) X poly(U)], an immunomodulator, has been shown to have antitumor effects in rodents and in a randomized clinical trial as an adjuvant to surgery in patients with operable breast cancer. The purpose of the present study was to determine the following: (a) clinical tolerance and safety of poly(A) X poly(U) in 13 patients with advanced cancer receiving a single dose of this duplex, using increasing amounts per intravenous injection of 90, 180, 300, and 450 mg; (b) if such high doses increased the level of interferon-mediated protein kinase and enhanced natural killer (NK) cell activity as observed previously with lower doses; and (c) if circulating interferon could be detected. No toxicity was observed in the 13 patients by close observation of clinical parameters, hemogram, and renal and liver functions. Increases of interferon-mediated protein kinase and of NK cell activity were observed, but there was no correlation between the magnitude of the responses and the dose of poly(A) X poly(U). No circulating interferon was detected. We conclude that poly(A) X poly(U) is not toxic in humans, at least up to a dose of 450 mg.

Drug Evaluation↗
PubMed1984

Adjuvant treatment with polyadenylic-polyuridylic acid in operable breast cancer: updated results of a randomised trial.

The results of a randomised trial of polyadenylic-polyuridylic acid given as adjuvant treatment for operable breast cancer were reviewed after a mean follow up period of 87 months. Of the 300 patients included in the original trial, 145 had been allocated to conventional treatment alone and served as controls. At the time of review the overall survival of the group given polyadenylic-polyuridylic acid was significantly improved (p less than 0.05) as compared with that of the controls given conventional treatment alone. Significant benefit (p less than 0.02) was also observed among patients with evidence of disease in lymph nodes, the best results occurring in those with up to three invaded nodes, who showed a significant increase in both overall and relapse free survival. No evidence of toxicity was recorded. These findings confirm the value of polyadenylic-polyuridylic acid as adjuvant treatment for operable breast cancer. Results in an experimental model and in patients receiving the adjuvant suggested a possible role of interferon and natural killer (NK) cells in the mechanism of action.

Breast Neoplasms↗
PubMed1984

A monoclonal antibody to the double-stranded polyribonucleotide complex poly(A) X poly(U).

A monoclonal antibody to the double-stranded polyribonucleotide complex poly(A) . poly(U) was derived from the fusion of spleen cells from immunized DBA/2 mice and the P3 X X63-Ag8 plasma cytoma. Specificity studies using radioimmunoassays showed that the anti-poly(A) . poly(U) does not cross-react with single-stranded polyribonucleotides. RNA X DNA hybrids or DNAs. In addition to RNA duplexes associating adenine and uracil, it recognizes synthetic poly(I) . poly(C) and naturally occurring reovirus RNA. It is thus directed against a conformational epitope with an absolute requirement for two polyribose phosphate chains. However, the antibody does not cross-react with poly(G) . poly(C) and is therefore able to distinguish between RNA double helices.

Animals↗
PubMed1984

[Does correction of reflux delay the development of renal insufficiency?].

Eighty patients have consulted for vesico-ureteric reflux over the past ten years, and the majority of them underwent surgery. Of these surgical patients, six presented with mild or acute renal failure. After a temporary aggravation of the renal failure, the antireflux procedure led to a prolonged stabilization of the renal function by eliminating the occurrence of acute recurrent pyelonephritis. Antireflux surgery would therefore seem justified and beneficial even in cases of renal failure.

Acute Kidney Injury↗
PubMed1983

Enhancement of natural killer cell activity and 2-5A synthetase in mice treated with polyadenylic.polyuridylic acid.

Previous studies have demonstrated that splenic natural killer (NK) cell activity of mice can be efficiently enhanced by polyadenylic.polyuridylic acid [poly(A).poly(U)]. Moreover, inoculation of mice with the duplex leads to the production of interferon (IFN). The NK boosting effect in mice was analyzed in parallel with the assay of an enzyme marker for the production and action of IFN, pppA(2'p5'A)n synthetase (2-5A synthetase). Kinetic studies revealed that splenic mononuclear cells of C3H/He mice inoculated intravenously with 10 micrograms or more of poly(A).poly(U) showed significantly enhanced cytotoxic activity in an in vitro 51Cr-release assay using NK sensitive YAC-1 target cells. Intravenous, intraperitoneal, and intramuscular administration of the duplex into mice were equally effective in obtaining such NK boosting effect. Furthermore, repeated weekly injections of poly(A).poly(U) did not induce resistance against NK boosting in the organisms. The levels of 2-5A synthetase in the organs, particularly spleens, of mice inoculated similarly with poly(A).poly(U) were greatly increased with a dose-dependent pattern. Repeated injections of mice with the duplex at 4-day intervals resulted also in significantly enhanced levels of splenic 2-5A synthetase after each injection. Thus, as a whole, enhanced NK activity accompanied increased levels of 2-5A synthetase in mice treated with poly(A).poly(U).

Adjuvants, Immunologic↗
PubMed1982

A new adjuvant treatment with polyadenylic-polyuridylic acid in operable breast cancer.

Adjuvant treatment with polyadenylic-polyuridylic acid poly A-poly U was tested in 300 patients with operable breast cancer who had all received the same locoregional treatment. They were randomized into two groups; 155 patients receiving 30 mg poly A-poly U i.v. once a week for 6 weeks and 145 controls. Overall survival was significantly improved in the poly A-Poly U group (P less than 0.05). The most striking difference (less than 0.03) was observed in the group of positive node patients, who had a 5-year relapse-free actuarial survival rate of 71% versus 47% in the controls.

Breast Neoplasms↗
PubMed1982

Enhancement of interferon-mediated protein kinase in mouse and human plasma in response to treatment with polyadenylic-polyuridylic acid (poly A:poly U).

Interferon-treated mouse and human cells show enhanced levels of kinase activity manifested by the phosphorylation of endogenous 67,000 (p67K kinase) and 72,000 (p72K kinase) molecular weight proteins, respectively. Both the p67K kinase and the p72K activities are detectable in mouse and human plasma. We have previously shown that the p67K kinase in the plasma of mice may serve as a marker for the presence and action of interferon. Here we show that these kinase activities are enhanced in mice and in patients treated with polyadenylic-polyuridylic acid (Poly A:Poly U) at doses (0.4-0.6 mg/kg body weight) which do not lead to detectable amount of circulating interferon. Mice injected with higher doses of Poly A:Poly U (2-10 mg/kg body weight) show detectable levels of circulating interferon in addition to enhanced levels of p67K kinase in their plasma. Interferon produced under these conditions is acid stable.

Adenocarcinoma↗
PubMed1982

Inhibition of C3H/He mouse mammary tumor growth by combined treatment with cyclophosphamide and polyadenylic-polyuridylic acid.

The antitumor effect of an immunomodulator, polyadenylic-polyuridylic acid, in combination with cyclophosphamide (CY) was studied in C3H/He mice bearing established mammary tumors. On Day 14 after tumor graft, mice received either CY (90 mg/kg) alone every 2 weeks for a total of four inoculations or alternate weekly inoculations of the same dose of CY and polyadenylic-polyuridylic acid (300 micrograms) or Bacillus Calmette-Guérin (400 micrograms) during 8 consecutive weeks. On Day 170, the following results were obtained. (a) Mice receiving CY alone showed significantly retarded tumor growth; nevertheless, 30 mice of 34 (88%) died of tumor, and only 1 mouse (3%) was tumor free. (b) In mice receiving combined CY and Bacillus Calmette-Guérin, no more significant tumor inhibition was observed than those receiving CY alone. (c) The most significant tumor inhibition was observed in mice receiving combined CY and polyadenylic-polyuridylic acid. Average tumor diameter on Day 63 was one-third (2 mm) of that of mice receiving CY alone (7 mm); 25 mice of 44 (57%) died of tumor; and 11 mice (25%) were tumor free. In in vitro 51Cr release assays using natural killer-sensitive YAC-1 target cells, cytotoxic activity of splenic nonadherent mononuclear cells of the tumor-bearing mice receiving the combined treatment was highly significantly increased. The importance of these findings relative to clinical application is considered.

Animals↗
PubMed1981

Altered RNA/protein ratio associated with the induction of differentiation of Friend erythroleukemia cells.

The synthesis and accumulation of RNA in Friend erythroleukemia (FL) cells induced to differentiate by treatment with the aminonucleoside of puromycin (AMS) or inhibited from differentiating by the addition of inosine to the medium were studied. When FL cells were grown in the presence of AMS, RNA synthesis was substantially inhibited. This effect could not be attributed solely to the inhibition of de novo purine synthesis because the biosynthesis of purine nucleotides from labeled inosine was much less depressed. The ratios of ATP to protein and of GTP to protein were slightly modified as compared to the untreated controls. However, the RNA/protein ratio was decreased. Thus, the RNA content of the cells was reduced 30-40%, but the protein content was not significantly affected. When the cells were treated with AMS together with inosine at a concentration that inhibits AMS-induced differentiation, the RNA/protein ratio was increased as compared with that found in cells treated with AMS alone and approached the level of the ratio in untreated control cells. Adenosine had a similar effect in overcoming the inhibition of RNA synthesis by AMS. Because the RNA/protein ratio of FL cells treated with dimethyl sulfoxide or sodium butyrate, two other potent inducers, was decreased by 44%, our results suggest that a correlation exists between the RNA content of the cells and the triggering of differentiation by inducers.

Adenosine↗
PubMed1980

Adjuvant treatment with polyadenylic-polyuridylic acid (Polya.Polyu) in operable breast cancer.

Adjuvant immunotherapy with polyadenylic-polyuridylic acid (PolyA.PolyU) was tested in a randomised trial on 300 patients with operable breast cancer, all of whom were treated by surgery with or without radiotherapy. They were randomly divided into an experimental group of 155 patients who were treated with 30 mg PolyA.PolyU intravenously per week for 6 weeks and a control group of 145 patients who received normal saline intravenously on the same schedule. The mean follow-up time was more than 50 months in both groups. The overall survival was significantly higher in the treated group (p less than or equal to 0.05), in whom the 5-year "relapse-free" surival was also increased. In node-positive patients, treatment increased the relapse-free survival (p less than or equal to 0.03) and overall survival (p less than or equal to 0.07). No side-effects were noted. Thus, immunotherapy with PolyA.PolyU appears to be a simple, non-toxic, and efficient adjuvant treatment in operable breast cancer.

Breast Neoplasms↗
PubMed1980

Electron microscopy of the reactions of anti-poly A. poly U and anti-poly I. poly C antibodies with synthetic polynucleotide complexes and natural nucleic acids.

The reactions between purified anti-poly A. poly U and-poly I. poly C. antibodies (IgG and IgM), and synthetic and natural polynucleotides were visualized at the molecular level. This was achieved by the use of fine tungsten bidirectional shadowing of molecules adsorbed onto thin carbon films, combined with dark field electron microscopic observation. A progression was observed from monogamous multivalency (binding of a single multifunctional antigen molecule with several combining sites of the same antibody molecule simultaneously) (Crothers and Metzger, 1972, Immunochemistry, 9, 341-357), to aggregation. Different types of figures were observed, among which loops formed by the coiling of the antigen around a single IgM molecule were very frequently seen. The tendency of IgG antibodies to bind cooperatively to certain antigens was also noted. In contrast, cross-links were seldom encountered. The cross-reactivity of different polynucleotides was also assessed by a quantitative analysis. The length of antigen associated to an antibody molecule (either IgG or IgM) was also measured.

Animals↗
PubMed1980

Induction of differentiation of murine erythroleukemia cells by aminonucleoside of puromycin and inhibition of this induction by purines and purine derivatives.

The effect of the aminonucleoside of puromycin (AMS) on Friend erythroleukemia cells in culture was investigated, because purines and purine analogues are known to act as inducers of differentiation. After treatment with 20-30 micro M AMS for 4 days, the cultures contained between 80 and 90% benzidine-positive cells. Stimulation of hemoglobin synthesis was dose and time dependent. Inosine had no stimulatory activity; however, when it was added to the medium together with AMS, erythroid differentiation was almost completely inhibited. The inhibitory effect of inosine on this potent inducer was also dose and time dependent. No cytotoxicity was observed with either compound, alone or in combination. Inhibition of AMS stimulation of erythroid differentiation was also observed in the presence of inosine monophosphate and poly(inosinic acid). Hypoxanthine had a dual effect. At high concentrations (500 microgram/ml) it acted as an inducer, but when added at low concentrations (20 microgram/ml) together with AMS it inhibited differentiation. These findings suggest there is a link between purine biosynthesis and the event(s) required to trigger differentiation. Agonist-antagonist activity of closely related biological compounds has thus been revealed in the erythroleukemia cells.

Animals↗
PubMed1979

Protective effect of immunization with nonviral antigens against Friend leukemia virus in mice.

DBA/2 mice immunized with poly(A).poly(U) complexed with methylated bovine serum albumin and emulsified in Freund's complete adjuvant were protected against challenge with Friend leukemia virus. There was no correlation between the level of antibody to the immunogen in the prechallenge serum and induced resistance to the virus. Although prechallenge sera of mice given the same amount of the duplex in a single inoculum bound 9.7% of poly(A).poly([(3)H]U) input, as compared to 45.3% bound by the prechallenge sera of mice given the immunogen in divided doses, both groups of mice were equally resistant to infection. Immunization with two other nonviral agents, bovine serum albumin fraction V or dinitrophenylated keyhole limpet hemocyanin, induced the same level of protection. A sparing effect of approximately 10(1.5) in infectivity was afforded the immunized mice. Immunization with either poly(A).poly(U) alone or with the carrier methylated bovine serum albumin was ineffective. In addition to antibodies to the respective immunogens, the prechallenge sera of the immunized mice also contained antibody to Friend leukemia virus gp71. The presence of such viral antibodies was not always related to resistance to infection by Friend virus. Some immunized mice that survived infection did not have gp71 antibody in their serum before challenge, and mice immunized with poly(A).poly(U) alone were susceptible to infection, although their prechallenge sera contained antibody to gp71. The mechanism involved in the induction of resistance to infection is not known. The effect may be mediated through a modification of the expression of both endogenous and exogenous type C viruses and affect immunological mechanisms controlling cellular responses.

Animals↗
PubMed1978

Randomized trial with Poly A-Poly U as adjuvant therapy complementing surgery in patients with breast cancer: in vitro study of cellular immunity.

The immunologic reactivity of patients with initially operable breast cancer was measured by the leukocyte migration inhibition test using autologous tumor extract (T), autologous serum (S), and a combination of both (T + S). These patients formed part of a randomized clinical trial comparing, on the one hand, conventional treatment and, on the other, conventional treatment complemented by injections of poly A-poly U. A sequential study was carried out on 159 patients, testing them 7 days, 2 months, 4 months, and 1 year after the operation. Statistical comparisons revealed no significant difference in the reaction of the two groups. In addition, no significant differences were found between those with lymph node involvement and those without. Radiotherapy given to those with lymph node involvement did not significantly change their reactions. We were able to show that the percentage of patients with a positive leukocyte migration inhibition test (LMIT) increases regularly and significantly with time. This study confirmed the presence in some autologous serum of a synergistic factor (SS factor) which increased the inhibition of migration of leukocytes by autologous tumor extract. This factor was found in 18 patients, equally divided between both therapeutic groups. In the group with SS factor, the percentage with lymph node involvement appeared greater (83% compared with 68% among those patients who had no SS factor), and the incidence of metastases was also increased (44% compared with 21%). This factor seemed to indicate a bad prognosis. However, there was a difference in the results between the two therapeutic groups in patients with the synergistic factor. Of nine patients undergoing conventional treatment, six had devleoped metastases, whereas only two out of the nine patients who also poly A-poly U developed metastases. The same trend was observed in the whole trial population.

Breast Neoplasms↗