Clinical Aspects of Resistance to Antineoplastic Agents

Skeel, Roland T.; Lindquist, C. A.

doi:10.1007/978-1-4615-6628-1_4

Cited by 4 publications

(2 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanism of GST-mediated resistance to adriamycin is more complex. This may well be related to the numerous possible mechanisms of action of this drug, which include activation to DNA-damaging agents, redox cycling, inhibition of topoisomerase II and effects on cell membranes (Kessel, 1989). GSH depletion appeared to influence adriamycin resistance mediated by the Alpha-class GST B Bi but did not affect the resistance mediated by GSTo, indicating that these proteins act by different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

Black

Beggs

Hayes

et al. 1990

Biochemical Journal

120

View full text Add to dashboard Cite

Adaptation and resistance to chemicals in the environment is a critical part of the evolutionary process. As a result, a wide variety of defence systems that protect cells against chemical insult have evolved. Such chemical resistance mechanisms appear to play a central role in determining the sensitivity of human tumours to treatment with chemotherapeutic drugs. The glutathione S-transferases (GST) are important detoxification enzymes whose over-expression has been associated with drug-resistance. In order to evaluate this possibility we have expressed the human Alpha-class and Pi-class GST cDNAs that encode GST B1B1 and GST pi in the yeast Saccharomyces cerevisiae. The expression of GST B1B1 or GST pi resulted in a marked reduction in the cytotoxic effects of chlorambucil, a bifunctional alkylating agent, and an anthracycline, adriamycin. These data provide direct evidence that the over-expression of GST in cells can confer resistance to anticancer drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

Black

Beggs

Hayes

et al. 1990

Biochemical Journal

120

View full text Add to dashboard Cite

show abstract

“…The tendency of eucaryotic cells to vary phenotypically is an important phenomenon in several biological systems, such as the progressive growth of malignant cells (23), the development of drug resistance in malignant cells (30), the phenotypic variation of cell lines in culture (6,29), and the differentiation of cells during normal development. Among the mechanisms that are known to contribute to this variability are base substitution (1,6,29), gene rearrangement (5), and gene amplification (28,32,33,42).…”

mentioning

confidence: 99%

Phenotypic variation associated with molecular alterations at a cluster of thymidine kinase genes.

Hardies¹,

Axelrod²,

Edgell³

et al. 1983

Mol. Cell. Biol.

View full text Add to dashboard Cite

Genetic variation was studied in several mouse L cell lines containing tandemly repeated herpes simplex virus thymidine kinase (TK) genes introduced by DNAmediated gene transfer. Variants were obtained after alternate positive and negative selection for TK expression. Three classes of molecular alteration are described. One class consisted of a concerted wave of hypermethylation affecting many sites in all or nearly all of the TK genes. This resulted in genetically stable TK-variants. Offive TK+ transformants from independent transfer experiments, only one, named HM, showed this class of methylation. Hypermethylation was a reproducible phenomenon in HM, yielding TK-variants after selection with either bromodeoxyuridine or acycloguanosine [Acyclovir or 9-(2-hydroxyethyoxymethyl)guanine]. A second class of alteration consisted of methylation affecting some, but not all, genes in the cluster. This happened in all TK+ (HAT [hypoxanthine-aminopterin-thymidinel-resistant) cell lines investigated, and this second class of methylation was incapable of generating TK-variants. Neither type of methylation was accompanied by genomic rearrangements. The third class of molecular alteration was found among TK+ (HAT-resistant) back revertants of hypermethylated HM TK-derivatives. It consisted of a 10-fold amplification of the hypermethylated TK genes. Demethylation of hypermethylated HM variants was not observed. Thus, hypermethylation in this system can be compensated for by amplification but cannot be reversed.We have used a model cell culture system to explore genetic mechanisms that alter gene expression in eucaryotic cells. A number of mouse L cell variants for expression from a thymidine kinase (TK) gene cluster were characterized in terms of gene copy number, gene arrangement, and DNA modification pattern. Three classes of molecular alteration are described here: two different patterns of DNA methylation, and gene amplification.The tendency of eucaryotic cells to vary phenotypically is an important phenomenon in several biological systems, such as the progressive growth of malignant cells (23), the development of drug resistance in malignant cells (30), the phenotypic variation of cell lines in culture (6,29), and the differentiation of cells during normal development. Among the mechanisms that are known to contribute to this variability are base substitution (1, 6, 29), gene rearrangement (5), and gene amplification (28,32,33,42).DNA methylation has also been broadly implicated in gene regulation, especially for X chromosome inactivation (18,20). A model has been proposed (16,27) in which modification of the DNA sequence to 5-methyl CpG in the recognition sites for regulatory proteins would block gene expression. Heritability of the methylation pattern and the resulting regulatory state would be provided by a maintenance system. After replication of symmetrically methylated CpG sequences, the maintenance system would specifically methylate the new strand in the halfmethylated replication product. Substantial evidence ha...

show abstract

Phenotypic Variation Associated with Molecular Alterations at a Cluster of Thymidine Kinase Genes

Hardies

Axelrod

Edgell

et al. 1983

Molecular and Cellular Biology

View full text Add to dashboard Cite

Genetic variation was studied in several mouse L cell lines containing tandemly repeated herpes simplex virus thymidine kinase (TK) genes introduced by DNA-mediated gene transfer. Variants were obtained after alternate positive and negative selection for TK expression. Three classes of molecular alteration are described. One class consisted of a concerted wave of hypermethylation affecting many sites in all or nearly all of the TK genes. This resulted in genetically stable TK- variants. Of five TK+ transformants from independent transfer experiments, only one, named HM, showed this class of methylation. Hypermethylation was a reproducible phenomenon in HM, yielding TK- variants after selection with either bromodeoxyuridine or acycloguanosine [Acyclovir or 9-(2-hydroxyethy-oxymethyl)guanine]. A second class of alteration consisted of methylation affecting some, but not all, genes in the cluster. This happened in all TK+ (HAT [hypoxanthine-aminopterin-thymidine]-resistant) cell lines investigated, and this second class of methylation was incapable of generating TK- variants. Neither type of methylation was accompanied by genomic rearrangements. The third class of molecular alteration was found among TK+ (HAT-resistant) back revertants of hypermethylated HM TK- derivatives. It consisted of a 10-fold amplification of the hypermethylated TK genes. Demethylation of hypermethylated HM variants was not observed. Thus, hypermethylation in this system can be compensated for by amplification but cannot be reversed.

show abstract

Clinical Aspects of Resistance to Antineoplastic Agents

Cited by 4 publications

References 104 publications

Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

Phenotypic variation associated with molecular alterations at a cluster of thymidine kinase genes.

Phenotypic Variation Associated with Molecular Alterations at a Cluster of Thymidine Kinase Genes

Contact Info

Product

Resources

About