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Biomedical subjects

W H McKenzie

Publications and source records attributed to W H McKenzie.

12 recordsLinked to original sources
PubMed1988

Sister chromatid exchange induction near the baseline with low doses of the alkylating agent CCNU.

Sister chromatid exchange (SCE) and cell-cycle kinetics were examined at near-baseline levels in human peripheral lymphocytes exposed to low doses of the potent SCE inducer 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), in vitro. A preliminary SCE dose-response curve was determined with a broad range of doses of CCNU using a single donor. SCE induction was approximately linear over the entire dose range from 5 to 200 microM CCNU. Cell cycle kinetics were retarded in a dose-dependent manner. A second dose-response curve from the same donor was constructed using several doses of CCNU between 0.5 and 10 microM to evaluate linearity and uniformity of SCE response near baseline levels. SCE induction was approximately linear between 1.0 and 10.0 microM CCNU. Finally, SCE and cell-cycle kinetics were examined in 12 donors at doses of 1.0, 5.0, and 10.0 microM CCNU to evaluate the reproducibility of near-baseline SCE induction over a range of subjects. Cell-cycle kinetics were retarded at all three doses with a highly significant increase in SCE frequencies at 5.0 and 10.0 microM CCNU. These data suggest that increases in SCE less than twice background can be reliable indicators of genotoxic exposure.

Cell Cycle↗
PubMed1988

Sister chromatid exchange in human lymphocytes exposed to ascorbic acid and the cancer chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

This study examines sister chromatid exchange (SCE) induction by ascorbate, a weak in vitro SCE inducer which acts through free radical intermediates, and low doses of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a potent SCE inducer which acts primarily through DNA interstrand cross-links. A small dose-dependent increase in SCE was observed in human peripheral lymphocytes exposed to ascorbate in the 0.5-10 mM dose range for 59 hours, with significant slowing of cell cycle kinetics at concentrations at and above 5 mM. CCNU concentration was selected to approximate the maximal increase in SCE induced by ascorbate. SCE frequencies in cells exposed sequentially to both agents were not significantly different from expectations under an additivity-of-effect model based on SCE response to each agent individually. Despite clear differences in the types of lesions induced, ascorbate and CCNU appear to act independently to induce SCE in a manner consistent with, though not exclusive to, Painter's replicon cluster model.

Adult↗
PubMed1988

Variable sister-chromatid exchange response in human lymphocytes exposed in vitro to gossypol acetic acid.

Gossypol has potential for widespread use as a male oral antifertility agent in humans since it appears to be highly efficacious, with reversible spermatostatic effects and minimal side effects. Furthermore, it is both inexpensive and readily available. Therefore, a thorough understanding of gossypol's genotoxic potential is critical. Although genotoxicity studies have produced conflicting reports, increased sister-chromatid exchange (SCE) and DNA-strand breaks have been reported in human cells exposed to gossypol in vitro. In the present study, SCE was examined in purified human lymphocytes and whole blood cultures exposed to gossypol acetic acid at various concentrations in serum-free medium. A small but statistically significant increase in SCE was observed in pooled analysis of 7 donors in whole blood cultures exposed to 0.70 microM gossypol acetic acid (p less than 0.02). Individual analyses revealed only one donor with a significant SCE response (p less than 0.001). In subsequent experiments, exposure at higher doses had no effect on SCE frequencies. A small but significant increase in SCE was observed in ficoll/hypaque purified lymphocytes exposed to 0.07 and 0.70 microM gossypol acetic acid. Interpretation of SCE data with variable response is discussed.

Cells, Cultured↗
PubMed1983

An analysis of the distribution and dose response of chromosome aberrations in human lymphocytes after in vitro exposure to 137Cesium gamma radiation.

The chromosome aberration yield for human lymphocytes exposed in vitro to various doses of 137Cesium has been studied. Dicentric, total acentric, and excess acentric data were seen to follow a Possion distribution. Calculated total hits demonstrated over-dispersion which could possibly be accounted for by a greater occurrence of single-hit phenomena being repaired than two-hit exchange processes. The resulting distribution generally contained an under-representation of cells with odd numbers of hits and an over-representation of zero- and even-hit classes as compared with Poisson predicted values. The relationship between dicentric yield and dose received in rads was fitted to the linear-quadratic formula Y = alpha D + beta D2 for dicentrics, yielding values of (20.1 +/- 3.8) X 10(-4) (aberrations/cell)/rad and (1.89 +/- 0.75) X 10(-6) (aberrations/cell)/rad2 for alpha and beta respectively. A plot of percent 'normal' cells versus the dose in rads resembled cell survival curves and was fitted to the relation P(D) = 100 e-Y where Y = alpha D + beta D2 with alpha = (23 +/- 11) X 10(-4) rad-1 and beta = (8.3 +/- 2.5) X 10(-6) rad-2. A possible use of scoring 'normal' cells for purposes of biological dosimetry is presented.

Adult↗
PubMed1983

Induction and reduction of sister chromatid exchange by CCNU in human lymphocytes in vitro.

Sister chromatid exchange (SCE) was studied in human lymphocytes treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in vitro. A dose-dependent increase of SCE was observed in cells exposed to 10(-5) - 10(-4) M CCNU. The maximal increase was 25-35 SCEs/cell over the control level, which is similar to the increase found in patients treated with CCNU in vivo. In the presence of rat liver microsomes (S-9 fraction) the frequency of CCNU-induced SCE was slightly higher than in parallel cultures without S-9, suggesting that microsomal metabolism may enhance the rate of decomposition of CCNU into reactive products. The CCNU-induced increase of SCE was greater in cells treated for longer time periods (up to 70 hr) than in cells subjected to a 1-hr treatment. This effect was most pronounced at higher concentrations of the drug (5 X 10(-5) M). The frequency of CCNU-induced SCE was also found to be dependent on the time of treatment in the cell cycle. A treatment for 1 hr during early G1-phase (about 20 hr before the first S-phase) gave rise to a higher increase of SCE than a 1 hr treatment immediately before or during the first or second S-phase. Thus, the CCNU-induced DNA damage leading to SCE seems to persist and may even increase during the prereplicative phase of the cell cycle. After replication in BrdUrd-free medium, the frequency of CCNU-induced SCEs decreased to the control level. The present results, taken together with other studies of strand break and cross-link formation by CCNU in mammalian cells in vitro, suggest that the major SCE-inducing damage by CCNU is DNA interstrand cross-links. These lesions then appear to be slowly removed, if at all, during the prereplicative phase of the cell cycle, and to disappear during or after replication in BrdUrd-free medium in vitro.

Biotransformation↗
PubMed1980

Cytogenetic study of a large black kindred: inversions, heteromorphisms, and segregation analysis.

Q-and C-band heteromorphisms were determined by sequentially staining cells from 81 members of an American Black kindred. The incidence of heteromorphs is reported for 14 people who married into the family. Small pericentric inversions of chromosome 3 were found in 23 kindred members, three of whom were homozygous. Six 'complete' chromosome 9 inversions and a single 'partial' inv9 were detected. there was no apparent phenotypic effect associated with the inversions, nor were duplication-deficiency chromosomes observed. Evidence for preferential segregation of Q-heteromorphs is reported, and comparison with data from other authors points to chromosome 13 as showing the most distortion.

Black People↗
PubMed1977

Cytogenetic effects of inhaled ozone in man.

Peripheral blood samples were collected from 30 normal male volunteers before and at intervals after inhaling 0.4 ppm ozone for 4 h. Data from 4 of the subjects were excluded from the analysis because of missing data points. The blood samples were cultured for 48 h, slides made and stained with a uniform Giemsa stain, and 100 metaphase spreads per subject per treatment scored for chromosome aberrations. Cells with suspected aberrations were photographed, destained, restained with a banding procedure and rephotographed to identify the specific chromosomes and regions involved. Pre-exposure, immediate post-exposure, 3 days post-exposure, 2 weeks post-exposure and 4 weeks post-exposure means for the percentage of cells with 46 chromosomes were 93.0, 93.6, 91.7, 94.5 and 94.2, respectively; in the same order, the mean number of cells with chromatid and/or chromosome breaks per order, the mean number of cells with chromatid and/or chromosome breaks per 100 cells was 0.96, 0.85, 1.00, 0.88 and 0.81 respectively, and for chromatid and/or chromosome gaps per 100 cells: 1.35, 0.96, 1.35, 0.81 and 0.77, respectively. The means for each of these parameters as well as the mean frequencies of complex aberrations are not statistically significantly different between blood sampling times. The distribution of aberrations by chromosome and light and dark bands is not significantly influenced by ozone exposure. These data indicate no apparent detectable human cytogenetic effect due to exposure to ozone under the conditions of this experiment.

Adult↗
PubMed1975

Human Q and C chromosomal variations: distribution and incidence.

Chromosome preparations of 77 normal newborn babies from Grand Junction, Colorado, were stained first for G-band identification of each chromosome and subsequently stained for Q- and C-band localization. This approach permitted determination of the variation of the C region size in all chromosomes, and is the first such study reported. A total of 391 Q and C variants was described, an average of 5.08 +/- 0.23 per subject; 225 were Q varients, 166 were C variants. Q varients were distributed among seven chromosomes in the genome and among 76 of the 77 subjects. Chromosomes 3 and 4 had variable Q intensities at the centromere, and the acrocentric chromosomes, 13, 14, 15, 21, and 22, had variable Q intensities in their short arms and/or satellites. C variants, though fewer in number, were more widely distributed in the genome, with at least one variant described in each chromosome. C variants were identified in 65 of the 77 subjects. Most unique were the six pericentric inversions found in chromosome 9. Except for giant satellites, no correlations were found between Q and C variants. Q and C variants evaluated in 16 members of four families showed that in nearly every case each variant observed in a child could be demonstrated in one or both parents. It is evident from this study that the magnitude of chromosomal variation in human populations is far greater than heretofore believed. It has also been shown that the combination of Q- and C-banding procedures will yield much more information than either technique used alone and is therefore the preferred approach to many population and gene localization studies.

Chromosome Mapping↗