RESUMEN

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 µm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 µm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

Asunto(s)

Nitroquinolinas/farmacología , Quinolonas/farmacología , Tripanocidas/farmacología , Catálisis , Células Hep G2 , Humanos , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Estructura Molecular , Nitroquinolinas/síntesis química , Nitroquinolinas/química , Nitroquinolinas/toxicidad , Paladio/química , Pruebas de Sensibilidad Parasitaria , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/toxicidad , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/toxicidad , Trypanosoma brucei brucei/efectos de los fármacos

RESUMEN

Some 16 nitroquinolines (NQs) and their fluorinated derivatives were tested for mutagenicity in Salmonella typhimurium TA100 without S9 mix to investigate the effect of fluorine-substitution on the mutagenicity. These NQs consist of 5-NQs, 5-nitroquinoline N-oxides (5-NQOs), N-methyl-5-nitroquinolinium methanesulfonates (N-Me-5-NQs) and 8-NQs, including three ortho-F-NQs, one meta-F-NQ, four para-F-NQs and four 3-F-NQs. For this purpose, eight F-NQs were newly synthesized. The data indicated that the ratio of the mutagenic activities (revertants/plate/nmol) of fluorinated NQs to those of the corresponding parent non-fluorinated compounds ranged from 0.6- to 119-fold. The fluorine atom located para to the nitro group markedly enhanced the mutagenicity (24-fold and more), while three ortho-fluorinated derivatives showed no significant increase in mutagenicity (enhancement ratio were 0.6, 0.8 and 1.7). With respect to 8-NQs, its meta-fluorinated derivative also had an enhanced mutagenicity over the parent compound (53-fold). In addition, although N-Me-5-NQ was less mutagenic than 5-NQ and 5-NQO, the mutagenicity of N-Me-5-NQ was most significantly enhanced by fluorine-substitution. These results suggest that introduction of a fluorine atom to the molecule in question may be a useful tool to modify their mutagenic potency and to better understand the mechanism of mutation.

Asunto(s)

Compuestos de Flúor/toxicidad , Nitroquinolinas/toxicidad , Cromatografía en Gel , Compuestos de Flúor/síntesis química , Espectroscopía de Resonancia Magnética , Pruebas de Mutagenicidad , Nitroquinolinas/síntesis química , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Relación Estructura-Actividad

RESUMEN

The 4-alkylamino-5-nitroquinolines (5NQs) are a new series of bioreductive drugs that exhibit varying degrees of selective toxicity (up to 60-fold) under hypoxic conditions in cell culture. This study tested the hypothesis that differences in hypoxia-selective cytotoxicity in this series reflect differences in the efficiency with which oxygen inhibits metabolic reduction. The products of reduction of six 5NQs were characterized and rates of reduction compared in aerobic and hypoxic AA8 cells. The major stable products of both radiolytic and metabolic reduction under anoxic conditions were the corresponding amines, which were not responsible for the toxicity of the parent nitro compounds. Metabolism of each compound was inhibited completely in aerobic cells, indicating that differences in hypoxia-selective toxicity in this series are not due to variations in efficiency as substrates for oxygen-insensitive nitro reduction. Rates of hypoxic metabolism correlated broadly with hypoxia-selective cytotoxicity; the 5NQ derivatives with high rates of hypoxic metabolism had good hypoxia-selective cytotoxicity, whereas the compounds with low rates of reduction (the 3,6-dimethyl and 8-methylamino compounds; 3,6diMe-5NQ and 8NHMe-5NQ) were non-selective. Low rates of drug-induced oxygen consumption by 3,6-diMe-5NQ and 8NHMe-5NQ in respiration-inhibited cells confirmed that these compounds are poor substrates for enzymatic nitro reduction. While there was an overall correlation between one-electron reduction potential at pH 7 (E1(7)) and rate of metabolic reduction, the relatively high E1(7) of 3,6diMe-5NQ (-367 mV) indicates that rates of reduction, and hypoxic selectivity of cytotoxicity, cannot be predicted from reduction potential alone. 3,6diMe-5NQ and 8NHMe-5NQ are cytotoxic through a non-bioreductive mechanism, the variable contribution of which may underlie the differences in hypoxia-selective cytotoxicity within this series of bioreductive drugs.

Asunto(s)

Aminoquinolinas/metabolismo , Nitroquinolinas/metabolismo , Aminoquinolinas/química , Aminoquinolinas/toxicidad , Animales , Biotransformación , División Celular/efectos de los fármacos , Hipoxia de la Célula , Línea Celular , Cricetinae , Cricetulus , Nitroquinolinas/síntesis química , Nitroquinolinas/química , Nitroquinolinas/toxicidad , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos

RESUMEN

The cytotoxic potency of 4-alkylamino-5-nitroquinoline drugs in AA8 cell cultures is enhanced up to 60-fold under hypoxia, with wide variations in selectivity for hypoxic cells observed for different members of this series. This study uses three representative 5-nitroquinolines to examine whether these differences in hypoxia-selective cytotoxicity are cell line specific, and to explore quantitatively the oxygen dependence of the cytotoxicity and metabolism of these compounds. The parent compound 5NQ, its 5NQ, its 8-methyl analogue (8Me5NQ) and the 8-methylamino analogue (8NHMe-5NQ) each showed similar hypoxic selectivity (ratio of concentration x time for 90% kill for zero versus 20% oxygen of 13-18-, 30-69- and 1.2-1.4-fold respectively in the three cell lines tested (AA8 Chinese hamster ovary, EMT6/Ak mouse mammary tumour and FME human melanoma). The cytotoxicity and metabolism (covalent binding) of radiolabelled 8Me-5NQ was investigated in AA8 cultures over a range of oxygen tensions (0-95%). The oxygen tension in solution required for 50% inhibition of log cell kill or adduct formation observed under anoxia (C50) was 0.01 and 0.02% oxygen respectively, suggesting that bioreductive alkylation is the mechanism of 8Me-5NQ toxicity. The K-value (oxygen concentration for cytotoxic potency equal to the mean of the potencies at zero and infinite oxygen) was similar (0.02% oxygen). Calculations based on measured rate constants for formation of the nitroradical anion of 8Me-5NQ and rates of radical loss through disproportionation or reaction with oxygen, predict a K-value for 8Me-5NQ of 0.025% oxygen, in good agreement with the experimentally determined value. Modelling of cell killing expected by the combination of 8Me-5NQ plus radiation suggested that tumour cells at intermediate oxygen tensions (0.01-1%) will be partially resistant to this treatment, and would limit the use of these 5-nitroquinolines in combination with radiation, unless sufficient drug could be delivered to cause extensive killing in the anoxic compartment.

Asunto(s)

Nitroquinolinas/farmacocinética , Nitroquinolinas/toxicidad , Oxígeno/metabolismo , Oxígeno/farmacología , Animales , Biotransformación , Células CHO/efectos de los fármacos , Células CHO/metabolismo , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula/fisiología , Cricetinae , Humanos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Nitroquinolinas/farmacología , Oxidación-Reducción

RESUMEN

The assessment of drugs designed to be useful in the eradication of hypoxic (resistant) cells involves comparison of hypoxic and aerobic radiosensitization, cytotoxicities, as well as DNA binding and reduction potentials. Three pairs of isomers of quinoline complexes [amino dichloro quinoline platinum (II)] were studied in this context. For the cis 5- and 6-nitroquinoline complexes, the DNA binding and toxicity were higher with the 5-substituted ligand. Reduction potentials were similar (-260 and -280 mV). No selectivity for hypoxic toxicity was observed, but radiosensitizing ability by both complexes was greater in hypoxic (than oxic) Chinese hamster ovary (CHO) cells. The trans 5-nitroquinoline complex produced better sensitization in hypoxia than its cis isomer [enhancement ratio (ER) 1.7 at 10 microM versus 40 microM for cis]. However, this was accompanied by some aerobic sensitization. The trans isomer of the (unsubstituted) quinoline complex was considerably more toxic than its cis isomer. Neither showed selectivity for hypoxia, either as radiosensitizers or as cytotoxins, which may be attributable to the lack of a reducible (nitro) function. Four quinoline complexes showed high activity in cisplatin-resistant L1210 cells, with the lowest resistance factor being for the trans quinoline complex. Results suggest that trans complexes with one aromatic ring may have activity different from the cis geometry, which should be exploited with respect to cisplatin resistance and cross-resistance with radiation.

Asunto(s)

Antineoplásicos/farmacología , Nitroquinolinas/farmacología , Compuestos Organoplatinos/farmacología , Quinolinas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Células CHO , Hipoxia de la Célula/fisiología , Cisplatino/farmacología , Cricetinae , Cricetulus , ADN/metabolismo , Isomerismo , Leucemia L1210/tratamiento farmacológico , Ratones , Nitroquinolinas/síntesis química , Nitroquinolinas/toxicidad , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/toxicidad , Quinolinas/síntesis química , Quinolinas/toxicidad , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/toxicidad , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

Infection with adeno-associated virus type 5 (AAV-5) reduced the number of mutants arising in the hypoxanthine phosphoribosyltransferase locus of human RD 176 cells after infection with herpes simplex virus type 1 (HSV-1; partially inactivated) or 4-nitroquinoline-1-oxide (4-NQO). The mutation frequency was reduced by AAV-5 infection from 11.4 to 1.8 after mutation with HSV-1 and from 3.2 to 2.5 when mutation was induced by 4-NQO. This was analyzed by determination of the number of cells resistant to 8-azaguanine when infected with AAV-5 prior to induction of mutations with HSV-1 or 4-NQO.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Dependovirus/fisiología , Hipoxantina Fosforribosiltransferasa/genética , Nitroquinolinas/toxicidad , Simplexvirus/fisiología , Azaguanina/farmacología , Resistencia a Medicamentos , Humanos , Hipoxantina Fosforribosiltransferasa/metabolismo , Pruebas de Mutagenicidad , Mutación , Células Tumorales Cultivadas , Replicación Viral

RESUMEN

Topical application on rat oral mucosa of the chemical 4-nitroquinoline 1-oxide (4NQO) has been shown to produce squamous cell carcinomas on the posterior tongue and/or the posterior hard palate. 4NQO is broken down in vivo by a diaphorase, 4NQO reductase (E.C.1.6.99.2), to produce an active molecule believed to be responsible for carcinogenesis. It has been shown that there are higher concentrations of 4NQO reductase in oesophageal mucosa compared with elsewhere in the gastrointestinal tract. The purpose of these experiments was to compare the distribution of certain diaphorases in the oral mucosa. Samples of rat tongue and cheek epithelia were homogenized, then ultracentrifuged to provide mixed cytosol and microsome fractions from the epithelial cells. A spectrophotometer was used to measure the variation in absorbance at 340 nm of NADH consumed by reduction of 4NQO by enzymes present in the tissue extracts. A histochemical technique was used to compare the activity of NADH diaphorase, NADP diaphorase and glucose-6-phosphate dehydrogenase at different sites of the oral mucosa. Statistical analysis showed that there were significant (P less than 0.01) differences between the activities of all three enzymes at different sites of the oral mucosa. In each case, a higher activity was found at the sites of high incidence of squamous cell carcinoma. A lower activity was found at sites where carcinomas did not occur.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Carcinoma de Células Escamosas/inducido químicamente , Mucosa Bucal/enzimología , NADH NADPH Oxidorreductasas/metabolismo , Nitroquinolinas/toxicidad , Neoplasias Palatinas/inducido químicamente , Neoplasias de la Lengua/inducido químicamente , Animales , Carcinoma de Células Escamosas/enzimología , Mejilla , Dihidrolipoamida Deshidrogenasa/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Masculino , NADPH Deshidrogenasa/metabolismo , Neoplasias Palatinas/enzimología , Hueso Paladar/enzimología , Ratas , Ratas Endogámicas , Lengua/enzimología , Neoplasias de la Lengua/enzimología

RESUMEN

A microplate version of the DNA-synthesis inhibition test (DIT) for fast detection of DNA-alteration potentials has been developed. The DIT is based on the concept that DNA damage causes inhibition of DNA synthesis that becomes detectable some time after replicating cells have been in contact with genotoxic agents. In this test procedure human tissue culture cells (HeLa S3), prelabeled with [14C]thymidine, arfe exposed for 90 min to the substances in question. After the cells are rinsed, they are allowed to recover for 2 1/2 h in fresh culture medium, thereby unspecific interactions interfering with DNA replication are practically eliminated. Next, [3H]thymidine is added for 30 min, and then the cells are harvested and thoroughly rinsed. Finally, incorporated radioactivity is determined by liquid scintillation counting for measurement of the 3H/14C ratio. This allows for the evaluation of DNA synthesis during the 3H-labeling period and of the extent of genotoxic damage. This microplate version of the DIT can be carried out fully automated in a laboratory workstation. The test is compared to other tests for genotoxicity. Its advantages are discussed.

Asunto(s)

ADN/genética , Pruebas de Mutagenicidad , Autoanálisis , Benzo(a)pireno/toxicidad , ADN/biosíntesis , Daño del ADN , Replicación del ADN , Células HeLa , Humanos , Mutágenos , Mutación , Nitroquinolinas/toxicidad

RESUMEN

The effects of the non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam and indomethacin on 4-nitroquinoline 1-oxide-(4-NQO)-induced tongue carcinogenesis in male ACI/N rats were examined. Rats were given 4-NQO (10 ppm) in the drinking water for 12 weeks and followed by either diet containing 150 ppm piroxicam or the drinking water containing 10 ppm indomethacin for 24 weeks. The incidence of tongue neoplasms (squamous cell papilloma and carcinoma) in rats given 4-NQO plus piroxicam (4/13, 31%) and those given 4-NQO plus indomethacin (3/13, 23%) were significantly lower than that of animals given 4-NQO alone (12/17, 71%) (P less than 0.05 and P less than 0.005). Rats given piroxicam or indomethacin alone had no neoplasms in the tongue. Thus, piroxicam and indomethacin significantly inhibited the development of tongue neoplasms in male ACI/N rats.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Indometacina/farmacología , Nitroquinolinas/toxicidad , Piroxicam/farmacología , Neoplasias de la Lengua/prevención & control , Animales , Masculino , Inhibidores de la Ornitina Descarboxilasa , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/prevención & control , Prostaglandinas/biosíntesis , Ratas , Ratas Endogámicas ACI , Lengua/patología , Neoplasias de la Lengua/inducido químicamente

RESUMEN

Dermal fibroblast strains from ataxia-telangiectasia (A-T) patients and clinically normal subjects were exposed to 4-nitroquinoline 1-oxide (4NQO) or its 3-methyl derivative (3me4NQO), and their colony-forming abilities and DNA metabolic properties were compared. Three A-T strains, i.e., AT2BE and AT3BI representing genetic complementation group AB and AT4BI belonging to group C, displayed enhanced (2.4- to 2.8-fold) sensitivity to reproductive inactivation by 4NQO, but exhibited normal survival in response to 3me4NQO. The initial induction and subsequent enzymatic repair of alkali-labile lesions (i.e., damaged sites converted to single-strand breaks in alkali) were quantitated by conventional velocity sedimentation analysis of cellular DNA in alkaline sucrose gradients. On exposure to concentrations of each chemical that produced comparable amounts of DNA damage, A-T and normal cells removed alkali-labile lesions at similar rates. However, the three 4NQO-sensitive A-T strains appeared to be defective in acting on alkali-stable adducts (formed by the parent compound but not its derivative), as judged by strand-break accumulation during posttreatment incubation with 1-beta-D-arabinofuranosylcytosine (araC). Specifically, the number of araC-detectable sites repaired in these A-T strains during the critical 2-h period immediately following 4NQO treatment ranged from 40 to 60% of that processed by normal controls. AT5BI, a fourth A-T strain assigned to complementation group D, responded normally to 4NQO-induced cytotoxicity and removed both alkali-labile and alkali-stable (araC-detectable) lesions normally. We thus conclude that the hypersensitivity of AT2BE, AT3BI, and AT4BI strains to 4NQO may be attributed, at least in part, to faulty execution of the excision-repair process operative on alkali-stable 4NQO adducts.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Ataxia Telangiectasia/genética , Supervivencia Celular/efectos de los fármacos , Reparación del ADN , Nitroquinolinas/toxicidad , Citarabina/farmacología , ADN/efectos de los fármacos , Daño del ADN , Reparación del ADN/efectos de los fármacos , Prueba de Complementación Genética , Humanos , Técnicas In Vitro

RESUMEN

Squamous metaplasia, dysplasia and carcinoma in situ (CIS) were induced in the ICR/Jcl mouse tracheal mucosa by exposure to a mist of 5% NaCl solution following single subcutaneous injection of 4-nitroquinoline 1-oxide (4-NQO). Either subcutaneous injection of 4-NQO or NaCl inhalation alone did not cause any marked change in the tracheal mucosa. The NaCl inhalation is considered to have promotion-like action on the mouse tracheal mucosa after administration of 4-NQO injection.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Carcinoma in Situ/inducido químicamente , Nitroquinolinas/toxicidad , Cloruro de Sodio/farmacología , Tráquea/patología , Neoplasias de la Tráquea/inducido químicamente , 4-Nitroquinolina-1-Óxido/administración & dosificación , Administración por Inhalación , Animales , Carcinoma in Situ/patología , Femenino , Inyecciones Subcutáneas , Pulmón/efectos de los fármacos , Pulmón/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Masculino , Metaplasia , Ratones , Ratones Endogámicos ICR , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/patología , Cloruro de Sodio/administración & dosificación , Tráquea/efectos de los fármacos , Neoplasias de la Tráquea/patología

RESUMEN

An established cell line of Chinese hamster ovary (CHO-9) cells and its UV-sensitive mutant 43-3B have been studied for the induction of cell killing, chromosomal aberrations and sister-chromatid exchanges (SCEs) after exposure to different types of DNA-damaging agents such as 4-nitroquinoline-1-oxide (4NQO), mitomycin C (MMC), diepoxybutane (DEB), methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS) and ethyl nitrosourea (ENU). In comparison with the wild-type CHO cells, 43-3B cells showed very high sensitivity to the UV-mimetic agent 4NQO and the DNA cross-linking agents MMC and DEB. The 43-3B cells responded with higher sensitivity to the monofunctional alkylating agents (MMS, EMS and ENU). The increased cytotoxic effects of all these chemicals correlated well with the elevated increase in the frequency of chromosomal aberrations. In 43-3B cells exposed to 4NQO, MMC or DEB the increase in the frequency of chromosomal aberrations was much higher than the increase in the frequency of SCEs (4-10-fold) when compared to the wild-type CHO cells. This suggests that SCEs are results of fundamentally different cellular events. The responses of 43-3B cells to UV, 4NQO, MMC and DEB resemble those of 2 human syndromes, i.e., xeroderma pigmentosum and Fanconi's anemia. These data suggest that 43-3B cells are defective in excision repair as well as the other pathways involved in the repair of cross-links (MMC, DEB) and bulky DNA adducts (4NQO).

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Alquilantes/toxicidad , Supervivencia Celular/efectos de los fármacos , Aberraciones Cromosómicas , Daño del ADN , Nitroquinolinas/toxicidad , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Línea Celular , Cricetinae , Cricetulus , Femenino , Ovario/citología

RESUMEN

A comparative study on the biological responses to different mutagens (UV, 4NQO, MMC, MMS and EMS) was made on CHO wild-type cells (CHO-9), its UV-hypersensitive mutant 43-3B, and 2 types of its transferants, i.e., one containing a few copies of the human repair gene ERCC-1 and the other having more than 100 copies of ERCC-1 (due to gene amplification). Cell survival, chromosomal aberrations and SCEs were used as biological end-points. The spontaneous frequency of chromosomal aberrations in the transferants was less than found in 43-3B mutant cells, but still 2-3 times higher than in wild-type CHO cells. The spontaneous frequency of SCEs in the transferants was less than in 43-3B and similar to that of wild-type cells. The induction of SCEs by all tested agents in transferants was similar to that found in CHO-9 cells, while the mutant is known to respond with higher frequencies. ERCC-1 also bestowed resistance to MMS and EMS on the mutant to induction of chromosomal aberrations and cell killing to levels comparable with those of the wild-type strain. On the other hand ERCC-1 could not completely regain the repair proficiency against cell killing and induction of chromosomal aberrations by UV or MMC to the wild-type level. These results suggest that the ERCC-1 corrects the repair defect in CHO mutant cells, but it is unable to rectify fully the defect; probable reasons for this are discussed. However, amplified transferants (having more than 100 copies of the ERCC-1 gene) restored the impaired repair function in 43-3B to UV-, MMC- or 4NQO-induced DNA damage better than non-amplified transferants with a few copies of the ERCC-1. This difference may be due to the high amount of gene product involved in the excision repair process in the amplified cells.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Alquilantes/toxicidad , Reparación del ADN , Nitroquinolinas/toxicidad , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Aberraciones Cromosómicas , Cricetinae , Prueba de Complementación Genética , Mutación , Intercambio de Cromátides Hermanas/efectos de los fármacos , Transfección , Rayos Ultravioleta

RESUMEN

Lymphoblastoid cell lines established from three unrelated kindreds with familial melanoma (FM) were cytogenetically analyzed for spontaneous and 4-nitroquinoline-1-oxide (4NQO)-induced chromosome aberrations. There were no significant differences between control, FM, or xeroderma pigmentosum (XP) cell lines for spontaneous aberrations. As a group, FM patients, as well as XP patients, had significantly higher 4NQO-induced aberrations than controls when metaphase cells were analyzed 2.5 hours after treatment during the G2 phase of the cell cycle. When selected cell lines were analyzed 18 hours after 4NQO treatment, the frequency of chromosome aberrations in FM cells returned to spontaneous levels, but XP cells retained significantly elevated aberration frequencies. The wide variability for chromosome aberrations within the control. FM relative, and FM patient groups during G2, however, indicated that analysis of total breakage rates alone would not be predictive of susceptibility to FM. Heterogeneity for carcinogen-induced chromosome breakage between some cancer-prone individuals and the possible significance of site-specific chromosome aberrations are discussed.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Aberraciones Cromosómicas/efectos de los fármacos , Melanoma/genética , Síndromes Neoplásicos Hereditarios/genética , Nitroquinolinas/toxicidad , Neoplasias Cutáneas/genética , Humanos , Interfase , Linfocitos/efectos de los fármacos , Linfocitos/ultraestructura , Células Tumorales Cultivadas/efectos de los fármacos , Xerodermia Pigmentosa/genética

RESUMEN

In vitro assays of the genotoxicity of quinoline compounds have yielded varying indications of their potency, and only limited determinations have been reported following in vivo administrations. We have quantified chromosome aberrations (CA) and sister chromatid exchanges (SCE) in the marrow cells of mice that had been injected with quinoline, 8-hydroxyquinoline, or 4-nitroquinoline-1-oxide up to levels approaching lethal. Treatments with quinoline produced no consistent increase in the number of aberrations at either 17 or 36 hr after treatment and no significant increase in SCE numbers at either 23 or 42 hr. Similarly, 8-hydroxyquinoline had no measurable effect on either CA or SCE but did tend to prolong the cell cycle. 4-Nitroquinoline-1-oxide was a very potent inducer of both CA and SCE as well as an inhibitor of cell division.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Médula Ósea/efectos de los fármacos , Hidroxiquinolinas/toxicidad , Mutágenos , Nitroquinolinas/toxicidad , Oxiquinolina/toxicidad , Quinolinas/toxicidad , Animales , Médula Ósea/ultraestructura , Línea Celular , Fenómenos Químicos , Química , Aberraciones Cromosómicas/efectos de los fármacos , Cricetinae , Cricetulus , Masculino , Ratones , Pruebas de Mutagenicidad , Intercambio de Cromátides Hermanas/efectos de los fármacos

RESUMEN

The SOS chromotest is a simple quantitative short-term bacterial assay for the detection of genotoxic activity of pure compounds or complex samples. On the basis of consecutive experiments aimed at demonstrating the relationship between the inoculum size and the outcome of the test using 4-nitroquinoline-1-oxide (4-NQO) as model genotoxin. It is shown that within the suitable range of the cell number there is a negative correlation between the number of tester cells and test sensitivity. Moreover, it could be demonstrated that the peak of the dose response curve, i.e., the maximal induction factor, is systematically influenced by the actual value of the ratio of beta-galactosidase to alkaline phosphatase enzyme activities at a 4-NQO concentration of zero. Last but not least, some simple statistical data describing the performance of the automated version of the SOS chromotest are also given.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Reparación del ADN/efectos de los fármacos , Pruebas de Mutagenicidad/métodos , Nitroquinolinas/toxicidad , Respuesta SOS en Genética/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Automatización , Interpretación Estadística de Datos , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , beta-Galactosidasa/metabolismo

RESUMEN

Normal rat oral keratinocytes have been transformed with the carcinogen 4-nitroquinoline N-oxide (4NQO) in vitro. The morphology, growth characteristics, ability to grow without anchorage and tumorigenicity in athymic mice was examined in 12 selected cell lines. Each of the lines could be assigned to one of two general groups. The first group of cell lines although showing some morphological signs of transformation and the ability to be subcultured beyond passage 15 were not anchorage independent or able to form tumours in athymic mice. The second group of cell lines showed distinct signs of morphological transformation, could be serially subcultured without 3T3 feeder cells, were anchorage independent and tumorigenic in athymic mice. Anchorage independence was more common at higher passages and with increased 4NQO treatment and correlated well with a decreased reliance on 3T3 feeder cell support. The anchorage-independent phenotype was closely associated with the ability to form tumours in athymic mice. This same sequence of phenotypic changes has been demonstrated in rat oral keratinocytes after 4NQO treatment in vivo indicating that during carcinogenesis, cell populations progress through the same stages whether proliferation occurs in vitro or in vivo. There is some evidence to suggest, however, that the time interval between stages may be altered when carcinogenesis takes place in vitro.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias de la Boca/inducido químicamente , Nitroquinolinas/toxicidad , Animales , Células Cultivadas , Células Epidérmicas , Epidermis/efectos de los fármacos , Queratinas , Masculino , Mucosa Bucal/citología , Mucosa Bucal/efectos de los fármacos , Ratas , Ratas Endogámicas

RESUMEN

The nitroreductase and acetyltransferase genes of Salmonella typhimurium TA1538 have been cloned into pBR322. When transformed into TA1538 derivatives, these plasmids provided the basis for an extremely sensitive assay for the detection of mutagenic nitroarenes.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Acetiltransferasas/genética , Compuestos Heterocíclicos/toxicidad , Pruebas de Mutagenicidad/métodos , Mutágenos/análisis , Nitrofurazona/toxicidad , Nitroquinolinas/toxicidad , Nitrorreductasas/genética , Oxidorreductasas/genética , Compuestos Policíclicos/toxicidad , Pirenos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Clonación Molecular , Nitrocompuestos/toxicidad

RESUMEN

Groups of 48 Wistar rats were subjected to thrice-weekly palatal application of the carcinogen 4-nitro-quinoline 1-oxide (4NQO) in propylene glycol 18, 12, 6 or 2 times, each 255 nmol 4NQO, in order to examine the relationship between the dose of the carcinogen and the tumour response. Other groups were treated with solvent alone or were left untreated. When the carcinogen was applied 18 or 12 times, squamous cell or verrucous carcinomas developed in 50% of the rats in 11 and 12 months, respectively, whereas rats subjected to the carcinogen 6 times demonstrated a 50% cancer rate in 23 months. Rats twice exposed to the carcinogen demonstrated a tumour rate of 25% in 30 months. Decreasing doses of 4NQO thus prolonged the latency period and decreased the tumour rate. The tumour development in the animals subjected to two carcinogen applications was significantly different from the tumour development among the solvent-treated animals, indicating that application of 255 nmol may approximate the initiating dose of 4NQO to be used in a two- or multi-stage carcinogenesis protocol. Most of the carcinomas, either squamous cell or verrucous, were located to the hard palate and to the gingival region of the upper jaw. Impaction of hair, bedding material and food was thought to promote the carcinogenic process.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Neoplasias de la Boca/inducido químicamente , Nitroquinolinas/toxicidad , Animales , Carcinoma de Células Escamosas/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Metástasis Linfática , Masculino , Neoplasias de la Boca/patología , Ratas , Ratas Endogámicas

RESUMEN

From a human cell line, RSb, with high sensitivity to the killing effects of 4-nitroquinoline 1-oxide (4NQO), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 254-nm ultraviolet light, a 4NQO-resistant variant, Qr-10, and an MNNG-resistant one, Gr-10, were established using ethyl methanesulfonate as the mutagen. Cell proliferation studies and colony-formation assays revealed that Qr-10 and Gr-10 cells actively proliferated under conditions where RSb cell proliferation was greatly inhibited by 4NQO and MNNG, respectively. Total cellular DNA synthesis, as estimated by [Me-3H]thymidine uptake into acid-insoluble cell materials, was depressed in 4NQO-treated Qr-10 and MNNG-treated Gr-10 cells as it was in chemical-treated RSb cells, but recovered more markedly from such inhibition in the variants. 4NQO- and MNNG-induced DNA-repair replication synthesis was enhanced to a greater extent in Qr-10 and Gr-10 cells, respectively, than in RSb cells. The Qr-10 and Gr-10 cells showed the same respective susceptibility to the effects of MNNG and 4NQO, on cell growth and DNA synthesis and DNA-repair synthesis as did the parent cells. But, Qr-10 cells had more resistance to UV-killing and higher levels of UV-induced DNA-repair synthesis than did RSb cells, while UV-susceptibility of Gr-10 cells was the same as that of the latter.

Asunto(s)

4-Nitroquinolina-1-Óxido/toxicidad , Daño del ADN , Metilnitronitrosoguanidina/toxicidad , Nitroquinolinas/toxicidad , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Línea Celular , Supervivencia Celular/efectos de los fármacos , ADN/biosíntesis , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Replicación del ADN/efectos de los fármacos , Replicación del ADN/efectos de la radiación , Resistencia a Medicamentos , Humanos , Rayos Ultravioleta