Cisplatin is a chemotherapeutic drug used to treat a variety of cancers. Both intrinsic and acquired resistance to cisplatin, as well as toxicity, limit its effectiveness. Molecular mechanisms that underlie cisplatin resistance are poorly understood. Here we demonstrate that deletion of the yeast CTR1 gene, which encodes a high-affinity copper transporter, results in increased cisplatin resistance and reduced intracellular accumulation of cisplatin. Copper, which causes degradation and internalization of Ctr1 protein (Ctr1p), enhances survival of wild-type yeast cells exposed to cisplatin and reduces cellular accumulation of the drug. Cisplatin also causes degradation and delocalization of Ctr1p and interferes with copper uptake in wild-type yeast cells. Mouse cell lines lacking one or both mouse Ctr1 (mCtr1) alleles exhibit increased cisplatin resistance and decreased cisplatin accumulation in parallel with mCtr1 gene dosage. We propose that cisplatin uptake is mediated by the copper transporter Ctr1p in yeast and mammals. The link between Ctr1p and cisplatin transport may explain some cases of cisplatin resistance in humans and suggests ways of modulating sensitivity and toxicity to this important anticancer drug.

https://www.pnas.org/content/pnas/99/22/14298.full.pdf

Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals

This paper reviews the ability of a number of chemicals to induce sister-chromatid exchanges (SCEs). The SCE data for animal cells in vivo and in vitro, and human cells in vitro are presented in 6 tables according to their relative effectiveness. A seventh table summarizes what is known about the effects of specific chemicals on SCEs for humans exposed in vivo. The data support the concept that SCEs provide a useful indication of exposure, although the mechanism and biological significance of SCE formation still remain to be elucidated.

Sister-chromatid exchanges: a report of the GENE-TOX program.

Sister chromatid exchanges (SCEs) represent the interchange of DNA replication products at apparently homologous loci. These exchanges presumably involve DNA breakage and reunion, although little is known about the molecular basis of sister chromatid exchange formation, and information about the biological significance of exchanges is largely circumstantial. In spite of these uncertainties, analysis of sister chromatid exchange formation in cytological systems has already provided information about chromosome structure and has been used to detect the effects of clastogens and to differentiate between chromosome fragility diseases.

Sister Chromatid Exchanges

The field of molecular epidemiology is very promising, as sophisticated techniques are being developed to address etiology, genetic susceptibility and mechanisms for induction of disease. The use of biomarkers plays a key role in these investigations because the information can be used to predict the development of disease and to implement disease prevention programs. However, as emphasized by Frederica P. Perera, the field is strewn with studies either that failed to use validated biomarkers or whose designs did not adequately consider the biology of the endpoints, and the availability of validated biomarkers of health risk is still limited. In this review, we have briefly described the usefulness of certain biomarkers for the documentation of exposure and early biological effects, with special concern for the prediction of cancer. An emphasis is placed on understanding the biological and health significance of biomarkers. By building reliable biomarker databases, a promising future is the integration of information from the genome programs to expand the scientific frontiers on etiology, health risk prediction and prevention of environmental disease.

Biomarkers in molecular epidemiology studies for health risk prediction.

The frequency with which diethylstilbestrol induces neoplastic transformation and somatic mutation was measured concomitantly in Syrian hamster embryo cells. While diethylstilbestrol was as active as benzo[a]pyrene in inducing transformation, it failed to induce mutations at two conventionally studied loci. These results suggest that diethylstilbestrol may transform cells in the absence of gene mutations.

https://science.sciencemag.org/content/sci/212/4501/1402.full.pdf

E. Gebhart

Papers

Bleomycin and sister-chromatid exchange in human lymphocyte chromosomes☆