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Dive into the research topics where Michael Hinds is active.

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Featured researches published by Michael Hinds.


Biochemical Pharmacology | 1992

Components of intrinsic drug resistance in the rat hepatoma

Amy L. Ellis; Craig E. Munger; Roderick T. Bunch; Karen E. Woods; Joyce K. Randolph; Lawrence Boise; Paul Swerdlow; Leonard A. Zwelling; Michael Hinds; Saul Yanovich; David A. Gewirtz

A carcinogen-transformed rat hepatoma cell line (Reuber H-35) was utilized as a model system for investigation of the biochemical factors which may limit the effectiveness of chemotherapy in intrinsically resistant tumors such as hepatocellular carcinoma. Northern blotting demonstrated expression of mRNA coding for the P-170 membrane-glycoprotein associated with the multi-drug resistance phenotype, while Western blotting identified the P-170 glycoprotein in the hepatoma cell membrane. Consistent with these observations, tumor cell sensitivity to the vinca alkaloids, vincristine and vinblastine, to the anthracycline antibiotics, Adriamycin and daunorubicin, and to the demethylepipodophyllotoxin derivative, VM-26, was enhanced by continuous incubation in the presence of the calcium channel antagonist, verapamil. Verapamil produced a minimal change in cell sensitivity to the demethylepipodophyllotoxin derivative, VP-16, and to the aminoacridine, m-AMSA. Relatively high detoxification potential via the glutathione metabolic pathway was also observed in the hepatoma cell. The capacity of topoisomerase II in nuclear extracts from the hepatoma cell to mediate cleavable complex formation stimulated by VM-26, VP-16 and m-AMSA appeared to be at least comparable to, if not greater than that from drug-sensitive HL-60 cells, suggesting that drug resistance may not occur at the level of this enzyme. Consistent with findings in a number of tumor cell lines resistant to antineoplastic drugs, the antiproliferative activity of the topoisomerase II inhibitors VM-26, VP-16 and m-AMSA appeared to be dissociable from the induction of DNA strand breaks, suggesting that such lesions in DNA may fail to fully account for the antiproliferative activity of these agents in the hepatoma cell.


Biochemical Pharmacology | 1993

Further characterization of an amsacrine-resistant line of HL-60 human leukemia cells and its topoisomerase II. Effects of ATP concentration, anion concentration, and the three-dimensional structure of the DNA target.

Janice Mayes; Michael Hinds; Laurie Soares; Elizabeth Altschuler; Paul Kim; Leonard A. Zwelling

The characterization of type II topoisomerases from amsacrine-sensitive (HL-60) and amsacrine-resistant (HL-60/AMSA) human leukemia cells was extended. The intercalator resistance and etoposide sensitivity of the HL-60/AMSA cells themselves were confirmed, and the stability of this pharmacologic phenotype over many hundreds of cell generations was demonstrated. Prolonging exposure of HL-60/AMSA cells to amsacrine did not alter their sensitivity relative to that of HL-60 cells. Improved methods of immunoblotting allowed clear demonstration that the topoisomerase II within these cells exhibited sensitivity and resistance characteristics that mirrored those of the cells and the isolated enzymes themselves. Additional biochemical characterization of the type II topoisomerases indicated that both enzymes relaxed supercoiled DNA in a distributive fashion and that the ATP concentrations at which optimal catalytic activity of the two enzymes was exhibited were identical. The enzymes differed, however, in their activity optima in buffers of various type and ionic strength. Furthermore, the inability of the HL-60/AMSA enzyme to exhibit enhanced DNA cleavage in the presence of amsacrine could be overcome if the DNA target molecule contained a bend cloned into its polylinker region. By contrast, a bend in a DNA plasmid containing no polylinker was resistant to amsacrine-enhanced cleavage in the presence of HL-60/AMSA topoisomerase II, as was a plasmid containing a polylinker with no bend. This suggests that an unusual DNA conformation (a bend) in a specific DNA context (a polylinker) may be a favored site for topoisomerase II action. It also suggests a mechanism by which the sites and extent of topoisomerase II activity can be controlled in cells.


Cancer communications | 1990

A restriction fragment length polymorphism for human topoisomerase II: Possible relationship to drug-resistance

Leonard A. Zwelling; Janice Mayes; Karl Deisseroth; Michael Hinds; Grace Grant; Sen Pathak; Fred D. Ledley; Rohini Vyas; Walter N. Hittelman

In previous studies we used Southern blotting to examine the topoisomerase II locus (on chromosome 17) in human leukemia cell lines and noted a difference in the XmnI restriction endonuclease digestion pattern between an m-AMSA-resistant line and its m-AMSA-sensitive parent line (Zwelling, L. A.; Hinds, M,; Chan, D.; Mayes, J.; Sie, K. L.; Parker, E.; Silberman, L.; Radcliffe, A.; Beran, M.; Blick, M. Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II. Journal of Biological Chemistry 264:16411-16420; 1989). We now demonstrate that the variable XmnI digestion pattern represents a normal restriction fragment length polymorphism (RFLP) which is observed in subjects without malignant disease and exhibits an autosomal pattern of inheritance. These data suggest that the previously described deviation in the genomic structure of topoisomerase II in the m-AMSA-resistant cell line did not reflect a new mutation, but rather a reduction to homozygosity at the topoisomerase II locus. This reduction to homozygosity is not due to chromosomal loss, as chromosome 17-specific gene probes clearly identify two chromosome 17s in the sensitive line and four in the resistant line, using chromosome painting with a chromosome 17-specific library. Some other genetic change must be the cause of the resistance of HL-60/AMSA and its topoisomerase II to the inhibiting actions of m-AMSA.


Biochemical and Biophysical Research Communications | 1988

Anion-dependent modulations of DNA topoisomerase II-mediated reactions in potassium-containing solutions

Leonard A. Zwelling; Diana Chan; Michael Hinds; Lynn Silberman; Janice Mayes

DNA binding proteins operate in an intracellular environment of low chloride concentration, yet in vitro assays of the activities of these proteins are often performed in isotonic chloride-containing solutions. Previously, the activity of bacterial DNA-binding proteins was found to be enhanced in potassium-containing solutions in which the anion glutamate (Glu) was substituted for chloride. We have extended this observation to include eukaryotic topoisomerase I and II activities. The concentration ranges over which DNA strand passing activities of these enzymes were observed was broader in KGlu than in KCl. This was also true for the topoisomerase II-mediated DNA strand passage and antineoplastic drug-dependent DNA cleavage produced by nuclear extracts from HL-60 human leukemia cells. The rate of topoisomerase II-mediated DNA strand passage was also dependent on anion moiety and concentration in potassium-containing buffers. Drug-dependent topoisomerase II-mediated DNA cleavage in intact HL-60 cell nuclei was also anion-dependent, suggesting that anion type and concentration may influence topoisomerase II-mediated events in mammalian cells as had been described for other DNA binding proteins in prokaryotic systems. This should be considered in developing biochemical assays of topoisomerase activities to reproduce intracellular conditions.


Biochemical Pharmacology | 1994

Phorbol regulation of topoisomerases I and II in human leukemia cells. Studies in an additional cell pair sensitive or resistant to phorbol-induced differentiation

Amy L. Ellis; Elizabeth Altschuler; Elise S. Bales; Michael Hinds; Janice Mayes; Laurie Soares; Theodore F. Zipf; Leonard A. Zwelling

We previously reported (Zwelling et al., Cancer Res 50: 7116-7122, 1990) that etoposide-induced DNA cleavage and mRNA coding for topoisomerase II are reduced in HL-60 cells induced to differentiate by phorbol ester. Reduction of etoposide-induced cleavage and topoisomerase II message did not occur in the derived cell line 1E3 (which is resistant to phorbol-induced differentiation), implying that topoisomerase II activity may be related to the state of cell differentiation. We have extended these studies using a new phorbol sensitive/resistant cell pair, S (sensitive) and PET (phorbol ester tolerant). Phorbol ester exposure not only reduced etoposide-induced DNA cleavage and topoisomerase II mRNA in S cells but also decreased the amount of immunoreactive topoisomerase II enzyme in whole S cells. However, immunoreactive topoisomerase II extracted from the nuclei of phorbol-treated S cells was not reduced compared with that from the nuclei of untreated S cells. This suggests that topoisomerase II contained in nuclear extracts is not always representative of the total cellular enzyme. Dramatic decreases in the amount, activity, or gene expression of topoisomerase II were not observed after phorbol treatment of the resistant PET cells; this is consistent with the potential involvement of topoisomerase II in monocytoid differentiation. Levels of topoisomerase I enzyme and mRNA fell in both S and PET cells after phorbol treatment; therefore, the genes for topoisomerases I and II did not appear to be regulated coordinately.


Cancer Chemotherapy and Pharmacology | 1991

The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells

Leonard A. Zwelling; Elizabeth Altschuler; Janice Mayes; Michael Hinds; Diana Chan

SummaryPhorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C, dramatically decreased topoisomerase II-reactive drug-induced DNA cleavage in HL-60 human cells. The effect of staurosporine, an inhibitor of protein kinase C, on drug-induced, topoisomerase II-mediated DNA cleavage was quantified in the same cells. Staurosporine decreased the magnitude of 4′-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)- and etoposide-induced DNA cleavage in a dose-and time-dependent fashion. Measurement of several parameters of cell proliferation revealed no clear and uniform correlation between staurosporines inhibition of these parameters and its effects on drug-induced DNA cleavage. A direct comparison with PMAs effects on drug-induced DNA cleavage showed that whereas PMAs inhibition of etoposide-induced cleavage was much greater than its inhibition ofm-AMSA-induced cleavage, the magnitude of staurosporines effect on the cleavage produced by the two topoisomerase II-reactive drugs was similar. Thus, although PMA stimulates protein kinase C and staurosporine inhibits this enzyme, it is unlikely that the actions of either on topoisomerase II-reactive, drug-induced DNA cleavage are mediated directly via protein kinase C. Furthermore, it is likely that the mechanisms by which PMA and staurosporine inhibit topoisomerase II-reactive drug-induced cleavage are different.


Biochemical Pharmacology | 1991

Effect of bryostatin 1 on drug-induced, topoisomerase II-mediated DNA cleavage and topoisomerase 11 gene expression in human leukemia cells

Leonard A. Zwelling; Diana Chan; Elizabeth Altschuler; Janice Mayes; Michael Hinds; George R. Pettit

Unlike PMA, bryostatin 1 has been found to have a minimal effect on drug-induced topoisomerase II-mediated DNA cleavage and no effect on topoisomerase II mRNA levels. Furthermore, bryostatin 1 overcame the down-regulatory effects of PMA treatment on (1) drug-induced, topoisomerase II-mediated DNA cleavage, (2) drug-induced cytotoxicity, and (3) topoisomerase II gene expression. Thus, it is unlikely that the effects of phorbol ester treatment on topoisomerase II-mediated events are a direct consequence of protein kinase C activation per se. Rather, the results with bryostatin 1 suggest that the phorbol ester effects are related to more distal effects of phorbol ester treatment that may be related to monocytoid differentiation.


Journal of Biological Chemistry | 1989

Characterization of an amsacrine-resistant line of human leukemia cells: evidence for a drug-resistant form of topoisomerase II

Leonard A. Zwelling; Michael Hinds; Diana Chan; Janice Mayes; Kiem Lan Sie; Elizabeth Parker; Lynn Silberman; A. Radcliffe; Miloslav Beran; Mark Blick


Cancer Research | 1991

Identification of a point mutation in the topoisomerase II gene from a human leukemia cell line containing an amsacrine-resistant form of topoisomerase II.

Michael Hinds; Karl Deisseroth; Janice Mayes; Elizabeth Altschuler; Ruud Jansen; Fred D. Ledley; Leonard A. Zwelling


Journal of the National Cancer Institute | 1990

HT1080/DR4: A P-Glycoprotein-Negative Human Fibrosarcoma Cell Line Exhibiting Resistance to Topoisomerase II-Reactive Drugs Despite the Presence of a Drug-Sensitive Topoisomerase II

Leonard A. Zwelling; Marilyn L. Slovak; James H. Doroshow; Michael Hinds; Diana Chan; Elizabeth Parker; Janice Mayes; Kiem Lan Sie; Paul S. Meltzer; Jeffrey M. Trent

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Leonard A. Zwelling

University of Texas MD Anderson Cancer Center

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Janice Mayes

University of Texas MD Anderson Cancer Center

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Elizabeth Altschuler

University of Texas MD Anderson Cancer Center

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Diana Chan

University of Texas MD Anderson Cancer Center

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Elizabeth Parker

University of Texas MD Anderson Cancer Center

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Laurie Soares

University of Texas MD Anderson Cancer Center

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Lynn Silberman

University of Texas MD Anderson Cancer Center

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Amy L. Ellis

University of Texas MD Anderson Cancer Center

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Fred D. Ledley

University of Texas MD Anderson Cancer Center

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