Biomedical subjects

A M Buller

Publications and source records attributed to A M Buller.

4 recordsLinked to original sources

PubMed2000

Genetic changes in solid tumors.

Although most solid tumors are treated surgically, determining the genetic changes present in the tumor of an individual patient is becoming increasingly important for managing the oncology patient. Our knowledge of the genetic alterations that characterize and predispose to solid tumors continues to expand. Concurrently, the advent of newer technologies such as DNA chips has the potential to enable a more rapid and comprehensive assessment of these changes. The ultimate goal of this new information and technology is to provide sensitive and specific tests that reduce unnecessary procedures and optimize therapy. This review addresses the utility of molecular testing in evaluating cancer. A review of the current technology and hereditary cancer syndromes is also presented.

Breast Neoplasms↗

PubMed1999

The roles of 5'-HS2, 5'-HS3, and the gamma-globin TATA, CACCC, and stage selector elements in suppression of beta-globin expression in early development.

The roles of HS2 and HS3 from the human beta-globin locus control region and of the TATA, CACCC, and stage selector elements of the gamma-globin promoter, in competitive inhibition of beta-globin gene expression in early development, were tested using stable transfections of HEL and K562 cells. Cells with an HS3gamma beta construct demonstrate that HS3 exhibits enhancing activity, but compared with HS2, this site participates less consistently in the inhibition of embryonic/fetal beta-globin expression. In cells with HS3HS2gamma beta constructs, the two HS sites act in concert to more effectively enhance gamma-globin gene expression and to drive stage-specific expression of the gamma- and beta-globin genes. A gamma-globin gene with a -161 promoter can competitively inhibit beta-globin gene expression. HS3HS2gamma beta constructs were used to determine the effects of gamma-globin promoter mutations within this region on competition. The CACCC and TATA elements, but not the stage selector element, inhibit inappropriate embryonic/fetal stage expression of the beta-globin gene. The mutation in the gamma-globin TATA element results in the use of two major alternative transcription start sites. The data suggest that proteins binding to the gamma-globin CACCC and TATA elements interact with those binding to HS2 and/or HS3 to preclude beta-globin transcription in early development.

Cell Line↗

PubMed1999

The gamma-globin promoter has a major role in competitive inhibition of beta-globin gene expression in early erythroid development.

The human gamma-globin gene competitively inhibits beta-globin gene expression in early erythroid development. To identify the gamma-globin gene sequences required for this effect, transgenic mice and stable transfection analyses with constructs containing 5'HS2 from the locus control region, modified gamma-globin genes, and the beta-globin gene were used. The -136 to +56 region of the gamma-globin promoter is necessary for competitive inhibition, as the beta-globin gene was inappropriately expressed in mouse embryos and in K562 and HEL cells containing constructs in which this region was deleted. Independently, the -140 to +56 region of gamma-globin gene was not sufficient to inhibit beta-globin transcription in mouse embryos or in cultured cells. Competitive inhibition of beta-globin gene expression was observed in K562 and HEL cells having a gamma-globin gene with a -161 promoter. The data suggest that the -161 gamma-globin promoter, which includes the CACCC box, two CCAAT boxes, the stage selector element (SSE), and TATA box, has a major role in suppressing beta-globin transcription early in development. Proteins binding to these or other gamma-globin promoter elements may interact with those binding to the locus control region, consequently precluding beta-globin transcription.

Animals↗

PubMedDate not supplied

A combination of hydroxyurea and isobutyramide to induce fetal hemoglobin in transgenic mice is more hematotoxic than the individual agents.

Pharmacologic agents such as hydroxyurea (HU), N, 3-4 trihydroxybenzamide (didox), and isobutyramide (ISB) can elevate gamma-globin as a potential treatment for the beta-hemoglobinopathies. In these experiments, transgenic mice with 5'HS2 from the human beta-globin locus control region, the fetal (A gamma), and adult (beta s) globin genes were used. Mice were treated with HU, didox, or ISB individually, or with combinations of HU or didox with ISB. The aim was to determine whether these drugs have synergistic effects on the induction of fetal hemoglobin (HbF) and whether the combination regimens are more hematotoxic. In the combination regimens, injections of HU or didox for five weeks were concomitant with ISB treatment every other day for the final three weeks of treatment. The combination of HU + ISB was more hematotoxic than the individual drugs based on significantly increased percentages of reticulocytes and reduced hemoglobin, indicating that caution should be taken in treatments involving combinations of these types of drugs. The didox + ISB combination was not more hematotoxic than the individual drugs. HbF was not induced in the groups treated with the combinations of HU or didox with ISB compared to the individual agents. There was a negligible effect on the percentage of HbF and an unexpected negative effect on the percentage of F cells. The results also have implications for future testing of HbF-inducing drugs in mouse models. In control mice that were phlebotomized but not treated with any drugs, increased percentages of F cells were observed, indicating that blood sampling can cause this effect. In addition, increases in the percentage of F cells did not correlate with increases in the percentage of HbF, indicating that monitoring F cells alone is not a sufficient measure of HbF induction.

Amides↗