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- W2012388512 abstract "The failure of chemotherapeutic agents to be highly effective against most human cancers is widely attributed to drug resistance (Curt et al., 1984; Goldie & Coldman, 1985). Resistance mechanisms are various and may result from selective pressures acting on a genetically unstable population. Resistance does not occur in normal renewal tissues and their sensitivity is dose limiting (Goldie & Coldman, 1985). It has recently been suggested that it might be possible to take advantage of the resistance of cancer cells and the sensitivity of normal cells to anti-cancer drugs (Bagshawe, 1986). Hydroxyurea (HU) which inhibits DNA synthesis probably through its action on ribonucleotide reductase (Ackerblom et al., 1981) is relatively ineffective against most solid cancers and resistance readily develops (Ariel, 1970). It was therefore suggested that treatment with inhibitors of DNA synthesis should cause more marked inhibition of DNA synthesis in normal renewal tissues than in resistant cancers. If so, then it might be possible to incorporate precursors of DNA that are cytotoxic, or suitable for scintigraphic imaging, selectively into tumour cell DNA. It was further suggested (Bagshawe, 1986) that this approach might be explored using the pyrimidine analogues 5-iodo-2'-deoxyuridine (IUdR) and 5-bromo-2'-deoxyuridine (BUdR) which differ from thymidine, the normal pyrimidine base, only by substitution of a halogen for the 5-methyl group. They compete with thymidine for phosphorylation and incorporation into DNA (Prusoff, 1959; Djordjevic & Szybalski, 1960). IUdR is rapidly dehalogenated unless incorporated into DNA but IUdR in DNA is retained until the cell divides or dies. IUdR and BUdR are known radioand photo-sensitisers (Djordjevic & Szybalski, 1960) and 12I-IUdR is a potent cytotoxic agent (Hofer, 1980). Preliminary experiments to test the hypothesis were performed in nu/nu mice carrying a human choriocarcinoma xenograft (CC3) (Figure 1 a-h). Group 1 (Figure la) received only 125I-IUdR and tissues excised 24h later showed, as have previous studies (Shuhmacher et al., 1974; Hampton & Eidinoff, 1961) that uptake of 125I-IUdR was -4 times greater in small intestine and colon than in tumour. When HU was given before 125I-IUdR (group 2, Figure lb) the total counts for intestinal tissues were substantially reduced but tumour counts were not reduced, indicating differential sensitivity to HU and suggesting that DNA synthesis continued in the tumour when it was suppressed in normal renewal tissues. Drugs which block thymidine synthesis increase utilisation of extracellular thymidine (Tattersall & Harrap, 1973) or thymidine analogue, probably through the thymidine salvage pathway (Sneider & Potter, 1969). They may reduce the thymidine pool (Tattersall & Harrap, 1973; Taylor et al., 1983) thereby favouring uptake of a thymidine analogue and" @default.
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- W2012388512 date "1987-03-01" @default.
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- W2012388512 title "A cytotoxic DNA precursor is taken up selectively by human cancer xenografts" @default.
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- W2012388512 doi "https://doi.org/10.1038/bjc.1987.58" @default.
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