Abstract
Normal human breast tissue maintained as xenografts in female Balb/c (nu/nu) athymic mice is capable of metabolising N-nitrosodimethylamine (NDMA) to active intermediates that will react with DNA. Administration of NDMA to mice with slow-release implants of 17 beta-oestradiol which provide human physiological (luteal phase) circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al., 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants. In mice with oestrogen implants, measurements of the amounts of the promutagenic lesion, O6-methyl-2'-deoxyguanosine formed in DNA clearly indicated a dose related increase in the extent of reaction. Detection of O6-methyl-2'-deoxyguanosine using immunohistochemical procedures revealed that the nuclei of cells of the glandular epithelium, supportive tissue and adipose tissue, in decreasing order of prevalence, were positively stained for the presence of this DNA lesion. Epithelial cells, which are the putative target cells for carcinogenesis in the breast, are therefore prone to promutagenic damage as a result of exposure to an environmental nitrosamine.
Highlights
Administration of NDMA to mice with slow-release implants of 1 7p-oestradiol which provide human physiological circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al, 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants
Much of the work carried out with xenografts has been directed towards assessing the responses of human tumours, to the effects of cytotoxic drugs (e.g. Schold et al, 1989; Rofstad, 1990), systems using normal human tissues provide opportunities to study effects of a variety of agents on human cells maintained and exposed under physiological conditions
Goat anti-rabbit immunoglobulins (GAR), normal goat serum (NGS) and horseradish peroxidase-anti-peroxidase (PAP) complex were supplied by Dako Ltd, High Wycombe, Bucks, UK
Summary
Administration of NDMA to mice with slow-release implants of 1 7p-oestradiol which provide human physiological (luteal phase) circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al, 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants. In mice with oestrogen implants, measurements of the amounts of the promutagenic lesion, 06-methyl-2'-deoxyguanosine formed in DNA clearly indicated a dose related increase in the extent of reaction. Detection of 06-methyl-2'-deoxyguanosine using immunohistochemical procedures revealed that the nuclei of cells of the glandular epithelium, supportive tissue and adipose tissue, in decreasing order of prevalence, were positively stained for the presence of this DNA lesion. Epithelial cells, which are the putative target cells for carcinogenesis in the breast, are prone to promutagenic damage as a result of exposure to an environmental nitrosamine
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