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PubMed1993

Insufficient inactivation of HIV-1 in human cryo poor plasma by beta-propiolactone: results from a highly accurate virus detection method.

Human cryo poor plasma was spiked with high titre HIV-1 and subjected to a beta-propiolactone (beta-PL) inactivation procedure. The residual titre of HIV-1 was measured using a sensitive and accurate titration technique based upon the killing of MT-4 cells by HIV and the subsequent inability to incorporate 3H-thymidine. It was found that under these conditions a reduction of only 1 log virus titre was achieved after one hour exposure to beta-PL and of 1.8 logs after 5 h. The presence of viable HIV was confirmed using immunohistochemical techniques, by transfer of live virus to fresh cells, and by production of reverse transcriptase. These results have obvious implications for products where human plasma is treated with beta-PL as the only virus inactivation step.

Blood↗
PubMed1995

Inactivation of DNA by beta-propiolactone.

beta-propiolactone (BPL) is an alkylating agent which reacts with many nucleophilic reagents including nucleic acids and proteins. BPL modifies the structure of nucleic acids after reaction mainly with purine residues (notably guanine). It induces nicks in DNA, cross-linking between DNA and proteins as well as between the DNA strands in the double helix. Consequently, BPL is widely used for the inactivation of viruses (DNA and RNA viruses). Moreover, it alters the capability of residual/contaminating cell DNA to be used as template by various polymerases. Thus, BPL reduces the risks associated with residual/contaminating cell DNA in biologicals.

Alkylating Agents↗
PubMed1998

Inactivation of viruses by beta-propiolactone in human cryo poor plasma and IgG concentrates.

Virus inactivation by cold treatment with beta-propiolactone (BPL) was investigated in human cryo poor plasma and purified IgG concentrates spiked with relevant human viruses or appropriate animal model viruses. The samples were treated with 0.1 or 0.25% BPL for 300 or 480 min, respectively. Residual infectivity was determined by standard microtitration assays on tissue culture cells. The inactivation of all viruses tested was more effective in IgG than in plasma. IgG: R1=4-5.5 log10 for vesicular stomatitis virus (VSV). Semliki Forest virus (SFV), bovine virus diarrhoea virus (BVDV), murine encephalomyelitis virus (MEV), feline calicivirus (FVC), suid parvovirus (PPV), simian virus 40 (SV40); R1=2-4 log10 for suid herpesvirus type 1 (SHV-1), bovine herpesvirus type 1 (BHV-1), human immunodeficiency virus type 2 (HIV-2), simian immunodeficiency virus (SIVagm3). Plasma: R1=3-5 log10 for VSV, SFV, BVDV, SHV-1, MEV:R1=0-3 log10 for HIV-1, SIVagm3 BHV-1, FCV, PPV, SV40. After addition of SIVagm3, HIV-2, and PPV to plasma or IgG, spontaneous inactivation without further addition of BPL was observed. These results demonstrate that treatment with BPL has a limited capacity to inactivate viruses. Different inactivation kinetics were observed in plasma and IgG concentrates. Therefore, virus inactivation by BPL must be tested for individual blood products independently and should not be extrapolated from other model systems.

Animals↗
PubMed1976

In vitro acylation of the xi-amino group of L-lysine in calf thymus histones by the carcinogen, beta-propiolactone.

We had previously reported that the carcinogen, beta-propiolactone (BPL) reacted in vitro with histones in whole mouse skin chromatin and that among the histone classes BPL was preferentially bound to the lysine-rich histones H1 and H1 degrees. In order to determine if in vitro reaction of BPL with calf thymus histones resulted in binding of BPL to L-lysine, we synthesized the model compounds XI-N-(3-hydroxypropionyl)lysine (HPL) and xi-N-(I-carboxyethyl)lysine (CEL) from BPL and L-lysine. The alpha-amino group of L-lysine was protected from reaction with BPL by the formation of a copper chelate. Structures were assigned on the basis of infrared spectra, pKa values and chemical analyses. BPL was reacted in vitro with calf thymus histones and the BPL-reacted calf thymus histones and control calf thymus histones were digested with trypsin followed by pronase. The respective digests were each chromatograhed on a column of AA-15 cation-exchange resin. The elution profiles of the two digests were very similar except for the appearance of a new ninhydrin-positive peak (NNPP) in the eluate of the trypsin-pronase digest of BPL-reacted calf thymus histones. When compounds HPL and CEL were added to the trypsin-pronase digest of control calf thymus histones and the mixture chromatographed on AA-15, both compounds were resolved from the other peptide (or amino acid) peaks. HPL was eluted in the same fractions as NNPP, HPL and NNPP exhibited identical RF values on silica gel TLC with acidic, alkaline and neutral solvents. CEL was not identified as a product of the reaction between BPL and calf thymus histones.

Animals↗
PubMed1977

In vitro binding of beta-propiolactone to calf thymus DNA and mouse liver DNA to form 1-(2-carboxyethyl) adenine.

In vitro reaction of beta-propiolactone (BPL) with calf thymus DNA and mouse liver DNA followed by acid (HCL) hydrolyses of the BPL-reacted DNA's resulted in the isolation of a new compound, 1-(2-carboxyethyl)-adenine (1-CEA). The structure was assigned on the basis of ultraviolet spectra at acidic, alkaline and neutral pH and electron impact and chemical ionization mass spectra as well as chemical synthesis of 1-CEA from BPL and 2'-adenosine-5'-monophosphoric acid. The only other compound previously isolated from the in vitro and in vivo reactions of BPL and DNA was 7-(2-carboxyethyl)guanine (7-CEG) which we also identified as a product of our in vitro reaction. Under the conditions used the main product of alkylation was 1-CEA and the ratios of the concentrations of 1-CEA to 7-CEG was approx 3 : 1. The possible effect of the formation of 1-CEA on the structure of DNA and its role in chemical carcinogenesis is discussed.

Adenine↗
PubMed1980

Esolation of 3-(2-carboxyethyl)thymine following in vitro reaction of beta-propiolactone with calf thymus DNA.

3-(2-Carboxyethyl)thymine (3-CET) was synthesized from beta-propiolactone (BPL) and dThd 5'P at pH 9.0--9.5 via the intermediate 3-(2-carboxyethyl)-thymidine-5'-monophosphoric acid (3-CEdThd5'P). 3-CEdThd5'P was converted to 3-CET by hydrolysis in 1.5 N HCl at 100 degrees C for 2 h. The structure of 3-CET was assigned on the basis of UV spectra, electron impact (EI) and isobutane chemical ionization mass spectra and the EI mass spectrum of a trimethylsilyl derivative of 3-CET. BPL was reacted in vitro with calf thymus DNA at pH 7.5. 100 A units of BPL-reacted DNA yielded, following perchloric acid hydrolysis and preparative paper chromatography, 3 A units of 3-CET. Reaction of BPL with the phosphodiester thymidylyl-(3'-5')-thymidine gave 3-(2-carboxyethyl)thymidylyl-(3'-5')-3-(2-carboxyethyl)-thymidine (approximately 3%). Phosphotriester formation was not detected.

Animals↗
PubMed1981

The isolation and characterization of 3-(2-carboxyethyl)cytosine following in vitro reaction of beta-propiolactone with calf thymus DNA.

The new adduct 3-(2-carboxyethyl)cytosine (3-CEC) was isolated following in vitro reaction of the carcinogen beta-propiolactone (BPL) with calf thymus DNA. The structure of 3-CEC was confirmed by synthesis from BPL and dCyd. Reaction of BPL with cCyd (pH 7.0-7.5, 37 degrees C) gave 3-(2-carboxyethyl)deoxycytidine (3-CEdCyd) (9% yield) and 3,N4-bis(2-carboxyethyl)deoxycytidine (3,N4-BCEdCyd) (0.6% yield). 3-CEdCyd and 3,N4-BCEdCyd were hydrolyzed (1.5 N HCl, 100 degrees C, 2 h) to 3-CEC and 3,N4-bis(2-carboxyethyl)cytosine (3,N4-BCEC), respectively. The structure of 3-CEC was assigned on the basis of UV and NMR spectra and the electron impact (EI) mass spectra of 3-CEC and a tri-trimethylsilyl (TMS) derivative of 3 CEC as well as deuterated (d27) tri-TMS derivative of 3-CEC. The structure of 3,N4-BCEC was assigned on the basis of UV spectra and the EI mass spectra of a tri-TMS derivative. Ei and isobutane chemical ionization mass spectra of 3-methylcytosine (3-MeCyt) and a di-TMs derivative of 3-MeCyt were obtained and were helpful in deducing the structures of 3-CEC and 3,N4-BCEC. This is the first report of the alkylation by BPL of an exocyclic atom on a base in DNA. Compound 3,N4-BCEC was not detected in BPL-reacted calf thymus DNA. The relative amounts of 1-(2-carboxyethyl)-adenine (1-CEA), 7-(2-carboxyethyl)guanine (7-CEG), 3-(2-carboxyethyl)-thymine (3-CET) and 3-CEC isolated from BPL-reacted DNA following perchloric acid hydrolysis were 0.23, 1.00, 0.39 and 0.41 respectively, when the alkylation reaction was conducted in phosphate buffer at 0-5 degrees C and pH 7.5 and 0.10, 1.00, 0.29 and 0.28 respectively when the reaction was conducted in H2O at 37b degrees C and pH 7.0-7.5.

Animals↗
PubMed1986

Effect of beta-propiolactone--an inhibitor of HTLV III/LAV activity--on immunological analyses.

beta-Propiolactone (BPL) inactivates LAV/HTLV III, the retrovirus associated with acquired immune deficiency syndrome (AIDS). Addition to specimens from patients with suspected AIDS or antibodies to LAV/HTLV III could reduce any occupational risk to laboratory staff. This study demonstrates that BPL treatment does not significantly affect the immunological analyses commonly required on these patients, namely measurements of serum immunoglobulins, complement components C3 and C4 and other serum proteins, detection of autoantibodies and estimations of T lymphocyte subpopulations.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Tissue-specific induction of mutations by acute oral administration of N-methyl-N'-nitro-N-nitrosoguanidine and beta-propiolactone to the Muta Mouse: preliminary data on stomach, liver and bone marrow.

We used the positive selection Muta Mouse model to detect organ-specific activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and beta-propiolactone (BPL), two highly reactive alkylating agents known to induce genetic damage and tumors in rodent stomach when administered orally. Seven days after a single oral administration of MNNG (100 mg/kg) or BPL (150 mg/kg), the mutation frequency in the Muta Mouse stomach increased significantly by 6.4-fold and 8.8-fold, respectively. A slight (1.8-fold) but significant increase in mutation frequency was also observed in the livers of BPL-treated mice, but not in the livers of MNNG-treated mice or the bone marrow of MNNG- and BPL-treated animals. These data indicate that the Muta Mouse model can be used to predict the gastric specificity of genotoxic carcinogens.

Administration, Oral↗
PubMed1979

Induction of sex-linked recessive lethals and autosomal translocations by beta-propiolactone in Drosophila: influence of the route of administration on mutagenic activity.

Beta-propiolactone (BPL) was tested for the induction of sex-linked recessive lethals and autosomal translocations in Drosophila melanogaster. The compound was administered to adult males either by oral application or by abdominal injection. When injected, BPL was a potent inducer of sex-linked recessive lethals. When BPL was given by feeding, its mutagenic activity was detectable only when the flies were starved and when the BPL-containing solutions were renewed several times. Nevertheless, the recessive-lethal frequency was one order of magnitude higher with injection. This difference in effects is attributed to (1) rapid decomposition of the compound in aqueous feeding solutions, and to (2) rapid degradation in vivo which restricts the activity of BPL mainly to the site of application. These data are compared with other studies in which both routes of application were applied. BPL induced translocations in stored spermatozoa when injected, but not when fed. This finding seems a logical consequence of (1) the difference in effectiveness of the two routes of application for BPL, and (2) the existence of different LECs for mutation induction (recessive lethals) and for chromosome breakage (translocations). In Drosophila, the breakage capacity of BPL was one order of magnitude lower than that of MMS, when a comparison was made on the basis of equal recessive-lethal frequencies.

Administration, Oral↗
PubMed1979

Antioxidants reduce the mutagenic effect of malonaldehyde and beta-propiolactone. Part IX. Antioxidants and cancer.

Increasing concentrations of malonaldehyde and beta-propiolactone were increasingly mutagenic with 7 mutants of Salmonella typhimurium, 5 of which mutated bya frameshift mechanism and 2 of which mutated through base-pair substitution. The antioxidants vitamin C, vitamin E, selenium and butylated hydroxytoluene (BHT) at 3 logarithmic concentrations markedly reduced mutagenesis in those strains which mutated by frameshift mechanism.

Ascorbic Acid↗
PubMed1987

The genotoxic effect of beta-propiolactone on mammalian oocytes.

beta-Propiolactone (beta PL) has been tested on preimplantation mouse embryos for possible genotoxic effects. Tests were performed at different stages of meiosis (late prophase I, diakinesis/metaphase I, anaphase I, telophase I/prophase II and metaphase II) by injecting females at various times after the induction of superovulation. Male and female derived chromosome complements from first-cleavage embryos were analysed before syngamy for cytogenetic abnormalities. A higher proportion of diploid oocytes, produced by the non-extrusion of the first or second polar body, was found after fertilization when the compound was administered immediately before metaphase I or II. No obvious effect was detected at any other time of beta PL exposure. Based on these results, several possible modes of action for beta PL are postulated.

Animals↗
PubMed1993

Principles of selective inactivation of viral genome. VIII. The influence of beta-propiolactone on immunogenic and protective activities of influenza virus.

The influence of beta-propiolactone action on the immunogenic and protective activity of the influenza virus A/WSN/33 (H1N1) has been studied. The production of antibodies against virion surface antigens in mice immunized intramuscularly by the modified virus was enhanced with the increase of inoculating dose from 6 x 10(7) to 1.5 x 10(8) viral particles per animal. The immunizing dose of 6 x 10(7) produced complete protection of immunized animals against a lethal challenge of A/WSN/33 virus. The inhibition of virus reproduction in animal lungs was increased with the increase of the virus immunizing dose up to 6 x 10(8). At a constant dose the inhibition of virus reproduction decreases with the increase of the virus modification extent.

Animals↗
PubMed1993

Beta-propiolactone treatment impairs the biological activity of residual DNA from BHK-21 cells infected with rabies virus.

The effects of beta-propiolactone (BPL), an alkylating and virus inactivating agent, on the structural and in vitro biological properties of different DNA preparations from BHK-21 cells were investigated. Both uninfected and rabies virus-infected cells were used. Purified cellular DNA (celDNA) was used as the reference, and supernatants from infected cells were treated with BPL. For structural and biological studies three types of DNA preparation were tested: celDNA; purified DNA from cell (infected or uninfected) supernatant (pcsDNA) with or without BPL treatment; and residual cell DNA present in purified rabies virus (inactivated or not) preparations. Rabies infection and BPL (diluted 1:4000) treatment induced modifications in the structure of the three DNA types, including strand breaks and nicks. The damage to the DNA structure by BPL modifies the biological properties of the pcsDNA appraised by its ability to serve as the template in vitro for different polymerases. When rabies virus was inactivated with BPL diluted 1:1000 the DNA damage increased dramatically: small double-stranded DNA fragments (50-200 base pairs) were generated which could not function as templates for polymerases.

Animals↗
PubMed1986

Enhancement of beta-propiolactone tumorigenesis in mouse skin by pretreatment with the anti-inflammatory steroid fluocinolone acetonide.

Using a two-step carcinogenesis protocol, SENCAR mice were initiated with 25 micrograms 7,12-dimethylbenz[a] anthracene (DMBA) and were then treated twice weekly with either (a) 0.5 mg beta-propiolactone (BPL) or (b) 1 microgram fluocinolone acetonide (FA) followed in 30 min by 0.5 mg BPL. The tumor incidence for the group receiving FA prior to BPL was significantly greater than for BPL alone (P less than 0.0005). Under these experimental conditions, BPL alone showed neither promoting activity nor complete carcinogenic activity. These results were not anticipated, but the reasons for their occurrence are being explored.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Efficacy and safety of two whole IgG polyvalent antivenoms, refined by caprylic acid fractionation with or without beta-propiolactone, in the treatment of Bothrops asper bites in Colombia.

The efficacy and safety of two whole IgG polyvalent antivenoms (A and B) were compared in a randomised, blinded clinical trial in 67 patients systemically envenomed by Bothrops asper in Colombia. Both antivenoms were fractionated by caprylic acid precipitation and had similar neutralising potencies, protein concentrations and aggregate contents. Antivenom B was additionally treated with beta-propiolactone to lower its anticomplementary activity. Analysing all treatment regimens together, there were no significant differences between the two antivenoms (A=34 patients; B=33 patients) in the time taken to reverse venom-induced bleeding and coagulopathy, to restore physiological fibrinogen concentrations and to clear serum venom antigenaemia. Blood coagulability was restored within 6-24 h in 97% of patients, all of whom had normal coagulation and plasma fibrinogen levels 48 h after the start of antivenom treatment. Two patients (3.0%) had recurrent coagulopathy and eight patients suffered recurrence of antigenaemia within 72 h of treatment. None of the dosage regimens of either antivenom used guaranteed resolution of venom-induced coagulopathy within 6 h, nor did they prevent recurrences. A further dose of antivenom at 6 h also did not guarantee resolution of coagulopathy within 12-24 h in all patients. The incidence of early adverse reactions (all mild) was similar for both antivenoms (15% and 24%; P>0.05).

Adolescent↗
PubMed1987

The role of specific IgE and beta-propiolactone in reactions resulting from booster doses of human diploid cell rabies vaccine.

Reactions after booster injections of human diploid cell rabies vaccine (HDCV) were investigated to determine the possibility of IgE-type antibody involvement. Although normal manufacture of HDCV involves the inactivation of the virus with beta-propiolactone (BPL), the effect of BPL on nonviral vaccine components, such as host cell components or stabilizing proteins, may be typical of the haptenic action of small molecular weight chemicals. Specific IgE to commercial HDCV preparations, BPL-treated preparations of noninfected host MRC5 cell sonicate (BPL-MRC5), and a human albumin (HA) (BPL-HA) used as a stabilizing agent were detected in sera from five individuals who reported reactions after booster doses of HDCV. However, these patients had no detectable IgE to normal HA. Sera from nonvaccinated individuals, vaccinated individuals who reported no reaction after HDCV booster, and pollen-allergic individuals had no detectable IgE to HDCV, BPL-MRC5, or BPL-HA. Changes in the ratios of pre- to postbooster serum levels of specific IgE to HDCV and BPL-HA were significantly different in a group of 19 individuals who reported reactions to HDCV boosters; these changes in pre- to postbooster IgE levels in nonreactive vaccinees were not significant. Prebooster serum IgE RAST ratios to HDCV or BPL-HA were not predictive of potential reactions to HDCV. A number of experimental BPL-HA reaction mixtures were assayed to examine the effect of variable concentrations of BPL to HA. Increasing relative molar concentrations of BPL to HA resulted in increased electrophoretic mobility, whereas the highest relative specific IgE binding was detected in BPL-HA molar reaction mixtures of approximately 12.5:1.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Specificity↗
PubMed1999

A model to study the effects of a viral inactivator (beta-propiolactone) on DNA ligation and gene expression in E. coli and Cos cells.

An experimental model to study the effects of viral inactivators on the biological properties of DNA was developed. Beta-propiolactone (betaPL) was used in this model and its effects on ligation, transfer and gene expression of naked DNA were assessed. Evidence that betaPL impairs these two major DNA functions are presented. The amounts of betaPL that alter or abolish gene expression and prevent DNA cohesive ends ligation were determined. Based on these observations, it was concluded that this experimental approach could be used to study the effects on the biological properties of DNA of other inactivators used in vaccine preparations.

Animals↗