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Biomedical subjects

G W Blair

Publications and source records attributed to G W Blair.

11 recordsLinked to original sources
PubMed1986

Resistance to adriamycin: relationship of cytotoxicity to drug uptake and DNA single- and double-strand breakage in cloned cell lines of adriamycin-sensitive and -resistant P388 leukemia.

Cloned lines of Adriamycin (ADR)-sensitive and -resistant P388 leukemia have been established from single cell cultures. A marker chromosome M1 was found in all cells in the heterogeneous resistant P388/ADR parental line as well as in the cloned resistant lines P388/ADR/3 and P388/ADR/7; a different marker chromosome M2 was present in the heterogeneous sensitive P388 parental line as well as the cloned sensitive line P388/4. Dose-survival studies showed that D0, the dose of Adriamycin reducing survival to 1/e (i.e., 37% of the initial population), was 33 +/- 5 (SE) nM for sensitive P388/4 cells, 169 +/- 17 nM for resistant P388/ADR/3 cells, and 336 +/- 28 nM for the more resistant P388/ADR/7 cells. Drug uptake in sensitive P388/4 cells was 1.6-fold greater than in resistant P388/ADR/3 cells and 2.1-fold greater than in resistant P388/ADR/7 cells. The number of DNA single-strand breaks produced per microM Adriamycin was 131 +/- 9 rad equivalents in sensitive clone 4 cells, 41 +/- 8 rad equivalents in resistant clone 3 cells, and 33 +/- 11 rad equivalents in resistant clone 7 cells. The number of DNA double-strand breaks per microM Adriamycin was 1721 +/- 126 rad equivalents in sensitive cells, 117 +/- 36 rad equivalents in resistant P388/ADR/3 cells, and 194 +/- 16 rad equivalents in resistant P388/ADR/7 cells. Differences in drug uptake were insufficient to explain the higher incidence of DNA single- and double-strand breaks in sensitive cells. These findings strongly support the concept that resistance to Adriamycin in P388 leukemia cells is multifactorial; however, this study did not resolve whether these changes arise from a single pleiotropic mutation or from multiple mutations. In sensitive P388/4 cells the number of DNA single-strand breaks formed could all be attributed to double-strand breaks. However, in both resistant cell lines the level of induction of single-strand breaks was in excess of that due to double-strand breaks, and this excess of single-strand breaks appeared to vary directly with the degree of resistance, being greater in the more resistant clone 7 cells than in the less resistant clone 3 cells. In both sensitive and resistant cell lines the ratio of true single- to double-strand breaks varied inversely with the concentration of Adriamycin. Finally, the cytotoxic activity of Adriamycin appeared to correlate more closely with formation of DNA double-strand breaks than with single-strand lesions.

Animals↗
PubMed1984

Quinone-induced DNA damage and its relationship to antitumor activity in L5178Y lymphoblasts.

The presence of a quinone group in the structure of a series of model compounds was shown to produce cell kill by a mechanism involving free radicals and active oxygen species. Furthermore, the ability of the compound to bind to DNA appeared to enhance its cytocidal activity. The same model compounds were used to investigate the effect of the quinone group on cellular DNA. DNA single-strand breaks, DNA double-strand breaks, and DNA-DNA cross-linking induced by the model compounds were measured by elution assays. Hydrolyzed benzoquinone mustard, which contains a quinone group, induced dose-dependent single-strand and double-strand breaks but no DNA cross-linking. Benzoquinone mustard, which possesses both a quinone moiety and an active alkylating group, produced dose-dependent DNA double-strand breaks but no apparent single-strand breaks. However, this compound produced significant levels of DNA cross-linking, a process which interferes with the assay for single-strand breaks. The relative activity of benzoquinone mustard in inducing DNA double-strand breaks was approximately 15,000-fold greater than that of hydrolyzed benzoquinone mustard. Aniline mustard, which has the same alkylating group as does benzoquinone mustard but no quinone function, produced lower levels of DNA-DNA cross-links and no DNA strand breaks. The induction of both DNA single-strand and double-strand breaks by hydrolyzed benzoquinone mustard was significantly inhibited by the cell-protective enzymes superoxide dismutase and catalase. The cytotoxic activity of hydrolyzed benzoquinone mustard appeared to correlate with the induction of DNA single- and double-strand breaks. These studies provided evidence that the presence of a quinone group in the chemical structure of a compound results in the production of DNA strand breaks. DNA damage was inhibited by superoxide dismutase and catalase, suggesting the involvement of free radicals and active oxygen species. The induction of DNA damage appeared to be enhanced by the ability of the compound to bind to DNA. The induction of strand breaks may correlate with the cytotoxic activity of the quinone agents.

Aniline Mustard↗
PubMed1972

Blood viscosity in multiple sclerosis.

Native blood from healthy subjects and from some pathological cases showed a fall in viscosity after the first passage through a stainless steel capillary viscometer in 97% of tests. Fortyfive blood samples from 27 active multiple sclerosis patients were tested. Blood from 19 of these patients showed no fall in viscosity.

Blood Viscosity↗