XP cells

The repair of particular Pt-DNA adducts has been an active area of research. In a study of the repair of interstrand cross-links, it was found that a CHO cell line hypersensitive to UV w as also very sensitive to cis-platin this cell line was less able to repair interstrand cross-links (87). Other investigators did not find such a correlation, however, and reported that interstrand cross-links were repaired more slowly in an FA cell line than in an XP cell line even though the XP cells were more sensitive to cis-DDP (98). Interstrand cross-links formed by trans-DDP were repaired more rapidly than those of c -DDP in CHO cells, implying that the persistence of the cir-DDP interstrand cross-links may be responsible for its cytotoxicity (99). Once again, however, the findings of these studies are equivocal since only one type of adduct was monitored without regard to other, more prevalent adducts. An in vitro repair assay using cis- and trans-... 

Finally, studies in the UV-sensitive XP cells also showed a divergence between SCE and chromosome aberrations. XP is abnormally sensitive to induction of chromosome aberrations by certain chemicals such as 4-nitroquinoline-1-oxide (4-NQO), whereas other chemicals such as A -methyl--nitro-A -nitrosoguanidine (MNNG) and ethyl methanesulfonate (EMS) produce the same amount of chromosome aberration in XP and normal cells. Wolff et showed that XP cells are consistently more sensitive than... 

Chemical mutagens induce a bewildering variety of lesions in DNA. Each chemical can be characterized by its own particular spectrum of these induced lesions and by the type of DNA repair that they elicit i.e., UV-like and X-ray-like chemicals induce long-patch and short-patch repair, respectively. XP cells are abnormally sensitive to UV-like chemicals in terms of chromosome aberrations and unscheduled DNA synthesis, but are as efficient as normal cells in repair of lesions induced by X-ray-like chemicals. The number of chemically induced lesions that give rise to SCE depends to some extent on the repair characteristics of the cell. XP cells are abnormally sensitive to both UV-like and X-ray-like chemicals in terms of SCE induction, and it has been suggested that SCEs are a sensitive indicator for the lesions that remain unexcised in the DNA. ... 

XP cells were obtained from the American Type Culture Collection. Cells with normal DNA repair were derived from foreskin material or skin biopsies... 

Simonshas recently demonstrated a similar biological recovery of XP cells from group D from 9 to 40% in 24 hr. However, Weichselbaum et... 

Comparative studies of the frequency of mutations to AG or TG resistance induced in normal and XP cells by exposure to V-AcO-AAF or to reactive metabolites of several carcinogenic polycyclic hydrocarbons, e.g., benzo[a]-... 

FIGURE 7. Comparison of the cytotoxic and mutagenic effect of increasing doses of UV irradiation in normal fibroblasts (NF) and in XP cells with no detectable excision-repair capacity (XP12BE) or able to carry out excision at a reduced rate (16% of normal) (XP12BE) See Section 2.2 for the procedures used to measure cytotoxicity and Section 2.3.1 for the in situ procedures used to detect the frequency of induction of mutations to AG resistance. Taken from Maher et with permission. 

XP cells are significantly more susceptible than are normal cells to the mutagenic action of these chemical carcinogens. 

FIGURE 1. Assay of repair replication by cesium chloride centrifugation. Diagrammatic representation of the results of a typical experiment with normal and XP skin cells. Note new incorporation of H-BrUra into region where old (parental) DNA sediments in normal cells (lower left panel) this is not present in XP cells (lower right panel). 

FIGURE 10. J llMw) response to 313-nm radiation after treatment with ICR-170 in normal and XP cells. Note similarity to jV-acetoxy-AAF (Fig. 11) and UV repair (Fig. 6). 

ICR-170 is an acridine with one nitrogen mustard group. It has been employed as an antitumor agent (Creech et al., 1972). In our repair assay, this agent induced repair events similar although not identical to those induced by jV-acetoxy-AAF (Fig. 10). ICR-170 differed from jV-acetoxy-AAF in that the size of the repaired regions with ICR-170 was smaller (approximately ten BrUra residues) than those with jV-acetoxy-AAF (approximately 25 BrUra residues). Nevertheless, ICR-170 clearly induces UV-type repair in normal cells and, like jV-acetoxy-AAF, defective repair in XP cells (see Section VI). 

Enough has been published on the hereditary disease xeroderma pigmentosum (XP), which causes extreme sensitivity to UV, that extensive explanation is not required here (Cleaver, 1968, 1969 Setlow et al., 1969 Regan et al., 97 a, b). When we observed the typical UV repair pattern in normal human cells after treatment with jV-acetoxy-AAF, we began to examine XP cells for their repair response to this carcinogen. Again the results were typical of those seen in UV experiments with XP cells i.e., there was little repair of the induced lesions (Fig. 11). We also examined the repair of UV-induced damage in a cell... 

The results with JV-acetoxy-AAF in XP cells led us to examine the response of XP cells to ICR-170, since UV-type repair was observed in normal cells after treatment with this agent. As expected, XP cells showed defective repair of lesions induced by ICR-170 (Fig. 10). 

FIGURE 12. Magnitude of repair in normal and XP cells after treatment with 4-NQO. 

Chemicals that induce UV-type repair in normal cells induce lesions that are essentially irreparable in XP cells. 

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