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Biomedical subjects

F Lavelle

Publications and source records attributed to F Lavelle.

71 records · Page 4Linked to original sources
PubMed1988

Differential sensitivity to pertussis toxin of 3T3 cells transformed with different oncogenes.

Pertussis toxin (PT), which blocks the activity of several G-proteins, has been found to exert a marked inhibitory effect on the DNA synthesis induced in 3T3 cells by serum or growth factors. 3T3 cells transformed with human c-ras oncogenes (Ha-ras, Ki-ras, N-ras) or with src, an oncogene coding for a protein kinase, have lost sensitivity to growth control by PT, even though substrates for PT can still be ADP-ribosylated in vivo. In contrast, 3T3 cells transformed with the SV40 virus behave like normal untransformed cells with respect to the ability of PT to decrease their growth rate. Oncogenes can thus likely be classified either as 'responders' or 'non-responders' to PT.

Animals↗
PubMed1987

Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones.

The systematic variation of the potent antitumor agent mitozolomide (1) is extended to cover alteration of substituents at positions 6 and 8 and to change the imidazo[5,1-d]-1,2,3,5-tetrazinone (1) skeleton to the isomeric pyrazolo-[5,1-d]-1,2,3,5-tetrazinone (17) skeleton. The series of eight 6-alkyl and 6-aralkyl derivatives of 1 showed optimal antitumor activity when the group was small or linear, but activity diminished as size and branching of this substituent increased. This may reflect altered transport characteristics, or failure of the enlarged derivatives to fit a binding site, or possibly a reduced tendency for the derivatives having bulky groups at position 6 to hydrolytically generate the putatively active triazenes (21). Testing of 14 derivatives of 1 differently substituted at position 8 revealed a complex structure-activity relationship, with good antitumor activity obtained for carbamoyl and sulfamoyl groups bearing small substituents. The 8-methylsulfonyl compound had noteworthy activity, but the 8-cyano, 8-nitro, and 8-phenyl derivatives were devoid of useful antitumor activity in these tests. From the limited number of pyrazolotetrazinones (17) reported here, it is suggested that the same conclusions as regards activity also hold true for this ring system.

Animals↗
PubMed1987

[Structure and activity of anthracyclines].

Several mechanisms are proposed for explaining the antitumor activity and the toxicity of anthracyclines. The first recognized biochemical target is DNA. Anthracyclines and DNA lead to the formation of complexes of intercalation. The intercalation can explain biochemical properties such as inhibition of DNA polymerase and of RNA polymerase. On the other hand, the intercalation cannot explain the chromosomal damages observed in cancer cells following in vivo administration or in vitro incubation. Additional mechanisms are proposed such as biological reduction of quinone C ring, leading to the formation of radical species able to react covalently with DNA. More recently, an interaction of anthracyclines with topoisomerase II has been also described. There is no clear correlation between antitumour efficacy and DNA intercalation. However it must be pointed out that no anthracycline has been found so far which shows antitumour activity dissociated from the ability of interacting with DNA. Anthracyclines interact with membranes: interaction with negatively charged phospholipids like cardiolipin; peroxidation of membrane lipids following biological reduction of the quinone C ring. These membrane effects are believed to be responsible for chronic cardiac toxicity. The clinical activity of daunorubicin and of doxorubicin leads to considerable work with the hope to discover more active and/or less toxic congeners. Several possibilities are investigated: isolation of new anthracyclines from natural sources (fermentation broths); chemical modifications of the whole molecule; total synthesis of new sugars and of new aglycones.

Antibiotics, Antineoplastic↗
PubMed1985

Synthesis and antitumor activity of 3'-C-methyl-daunorubicin.

Reaction of 1,5-anhydro-4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoro-acetami no-L-lyxo-hex-1-enitol with daunomycinone in the presence of anhydrous toluene-p-sulfonic acid in benzene, followed by removal of the N- and O-protecting groups under mild conditions, gave 3'-C-methyldaunorubicin. The antitumor activity of the new anthracycline glycoside has been evaluated.

Animals↗
PubMed1985

Iron(III)-adriamycin and Iron(III)-daunorubicin complexes: physicochemical characteristics, interaction with DNA, and antitumor activity.

Fe(III) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric and spectroscopic measurements, we have shown that adriamycin and daunorubicin form two well-defined species with Fe(III), which can be formulated as respectively Fe(HAd)3 and Fe(HDr)3. In these formulas, HAd and HDr stand for adriamycin and daunorubicin in which the 1,4-dihydroxy-anthraquinone moiety is half-deprotonated. Both complexes are six-membered chelates. The stability constant is beta = (2.5 +/- 0.5) X 10(28) for both complexes. Interaction with DNA has been studied showing that, despite strong coordination to Fe(III), anthracyclines are able to intercalate between DNA bases pairs, releasing the metal. These complexes display antitumor activity against P 388 leukemia that compares with that of the free drug. Fe(HAd)3, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. Moreover, it is shown that the triferric adriamycin compound so called "quelamycin" is in fact a mixture of Fe(HAd)3 and polymeric ferric hydroxide.

Circular Dichroism↗
PubMed1985

[Use of permeabilized cells in the study of inhibitory products of herpes virus replication].

Cells made permeable by exposure to lysolecithin following infection by HSV-1 synthesize DNA (in greater amounts than non-infected cells) in the presence of the four deoxyribonucleoside-triphosphates (dNTPs) : dATP, dCTP, dGTP, and dTTP. DNA synthesis also occurs if dTTP is replaced by dT or dTMP, indicating activity of enzymes such as thymidine kinase, thymidylate kinase, deoxyribonucleoside-diphosphate kinase and ADN polymerase. Examination of DNA synthesis in permeabilized cells enables detection of antiviral activity of agents incapable of penetrating into intact cells and therefore ineffective in cell cultures. No detectable protein-tyrosine kinase activity was found in HSV-1 infected cells.

Antiviral Agents↗
PubMed1985

Experimental antitumor activity against murine tumor model systems of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one (mitozolomide), a novel broad-spectrum agent.

8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H) -one (mitozolomide) demonstrates curative action against a range of murine tumor model systems. At single doses of between 20 and 40 mg/kg, the latter of which approximates the 10% lethal dose value in mice, the compound elicited cures against the L1210 and P388 leukemias irrespective of the route of tumor and/or drug administration; in these tests, animals receiving 10(5) cells i.p. survived greater than 60 days after treatment. Potent effects were also observed against the TLX5 lymphoma (s.c.) and B16 melanoma (i.p.). In other experiments, 7 of 10 animals implanted with 2 X 10(5) Lewis lung carcinoma cells survived greater than 60 days while 10 of 10 animals survived greater than 60 days after implantation of the Colon 26 tumor. Potent inhibition of the solid tumor models was also observed with complete cures of the Colon 38, M5076 sarcoma, and ADJ/PC6A plasmacytoma. In cross-resistance studies, the compound was ineffective against an L1210 leukemia made resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea and against a TLX5 lymphoma resistant to dimethyltriazenes but cured animals bearing the L1210 leukemia with derived resistance to cyclophosphamide.

Animals↗
PubMed1980

Experimental and clinical activity of a new anthracycline derivative: detorubicin (14-diethoxyacetoxydaunorubicin).

This report concerns the experimental activity and the preliminary clinical results obtained with detorubicin, an anthracycline. Experimentally, in comparison with doxorubicin, detorubicin is less toxic, less immunodepressive, and less mutagenic, its experimental antitumor activity is equal or superior, and differences are found in pharmacokinetics. Its most interesting activities in clinical cancer therapy are found in non-Hodgkin lymphomas, in carcinomas, and in soft-tissue sarcomas.

Animals↗
PubMed1977

The involvement of the bridging imidazolate in the catalytic mechanism of action of bovine superoxide dismutase.

The pulse-radiolysis method has been used to study the catalytic mechanism of O2 leads to dismutation by the Co(II)-substituted bovine erythrocuprein (superoxide dismutase, EC 1.15.1.1). Catalysis is accompanied by spectral changes that may be interpreted in terms of rapid protonation and deprotonation of the Cu-facing nitrogen atom of the imidazolate that bridges the Cu(II) and the Co(II) [or Zn(II)] in the oxidized enzyme. This rapid change permits the possibility that the imidazole is a proton donor in the catalytic reduction of O2 leads to.

Animals↗
PubMed1977

A pulse-radiolysis study of the manganese-containing superoxide dismutase from Bacillus stearothermophilus. A kinetic model for the enzyme action.

The enzymic reaction mechanism of a manganese-containing superoxide dismutase from Bacillus stearothermophilus was studied by using pulse radiolysis. During catalysis (pH 8.9; 25 degrees C), changes occurring in the kinetics of substrate disappearance and in the visible absorption of the enzyme at 480 nm established that the simple two-step mechanism found for copper- and iron-containing superoxide dismutases is not involved. At a low ratio (less than 15) of substrate concentration to enzyme concentration the decay of O2--is close to exponetial, whereas at much higher ratios (greater than 100) the observed decay is predominantly zero-order. The simplest interpretation of the results invokes a rapid one-electron oxidation-reduction cycle ('the fast cycle') and, concurrently, a slower reaction giving a form of the enzyme that is essentially unreactive towards O2-- but which undergoes a first-order decay to yield fully active native enzyme ('the slow cycle'). The fast cycle involves the native enzyme EA and a form of the enzyme EB which can be obtained also by treating the form EA with H2O2. Computer calculations made with such a simple model predict behaviour in excellent agreement with the observed results.

Catalysis↗
PubMed1977

A pulse-radiolysis study of the catalytic mechanism of the iron-containing superoxide dismutase from Photobacterium leiognathi.

The mechanism of the enzymic reaction of an iron-containing superoxide dismutase purified from the marine bacterium Photobacterium leiognathi was studied by using pulse radiolysis. Measurements of activity were done with two different preparations of enzyme containing either 1.6 or 1.15 g-atom of iron/mol. In both cases, identical values of the second-order rate constant for reaction between superoxide dismutase and the superoxide ion in the pH range 6.2-9.0 (k=5.5 X 10(8) M-1-S-1 at pH 8.0) were found. As with the bovine erythrocuprein, there was no evidence for substrate saturation. The effects of reducing agents (H2O2, sodium ascorbate or CO2 radicals) on the visible and the electron-paramagnetic-resonance spectra of the superoxide dismutase containing 1.6 g-atom of ferric iron/mol indicate that this enzyme contains two different types of iron. Turnover experiments demonstrate that only that fraction of the ferric iron that is reduced by H2O2 is involved in the catalysis, being alternately oxidized and reduced by O2; both the oxidation and the reduction steps have a rate constant equal to that measured under turnover conditions. These results are interpreted by assuming that the superoxide dismutase isolated from the organism contains 1 g-atom of catalytic iron/mol and a variable amount of non-catalytic iron. This interpretation is discused in relation to the stoicheiometry reported for iron-containing superoxide dismutases prepared from several other organisms.

Ascorbic Acid↗
PubMed1975

[Purification and study of two superoxide dismutases of the mushroom Pleurotus olearius].

Two different superoxide dismutases have been purified from the luminous fungus Pleurotus olearius. The second enzyme SODm presents structural differences with the first enzyme SODc previously described [5]: it has a molecular weight of 78,000 and is composed of identical subunits (20,000); it contains also two functional Mn atoms. Using an antiserum prepared against SODc, we have shown that there is no cross-reaction between these two proteins. Spectral studies of the first enzyme SODc suggest that the active center contains trivalent manganese Mn-III.

Agaricales↗