RESEARCH & DEVELOPMENT Recognition proteins could increase cisplatin serStivity It may be possible to sensitise cells to cisplatin by increasing the concentration of structure-specific recognition proteins which bind to the major cisplatin-DNA adducts, suggest researchers from the Massachusetts Institute of Technology, US. To be clinically significant for the treatment of cisplatin-resistant tumours, such an approach would only need to increase sensitivity by 2- or 3-fold, they say. These researchers cloned and sequenced a yeast gene, IXR I, encoding the structure-specific recognition protein, Ixrl. This protein was shown to bind specifically to cisplatin-modified DNA, but not to unmodified DNA or DNA modified by an inactive platinum compound. Further investigation supported the concept that this protein is involved in mediating the cytotoxicity of cisplatin. A mutant yeast strain lacking the IXRI gene was only half as sensitive to the cytotoxicity of cisplatin. This decreased sensitivity correlated with a reduction in the amount of bound cisplatin on DNA in the mutant cells. The researchers suggest that structure-specific recognition proteins shield DNA-containing intrastrand crosslinks formed by cisplatin from DNA repair enzymes. However, other explanations for the proteins effects are also plausible. Brown Sl. Kellett Pl. Lippard Sl. Ixr I. a yeast protein that binds to platinated DNA and confers sensitivity to cisplatin. Science 261: 603-605. 30 lui 1993 80021.379 ISSN 0156-2703/9310828-0091$1.000 Adla lntern8tlonal Ltd 9 Aug 1993

Recognition proteins could increase cisplatin sensitivity

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RESEARCH & DEVELOPMENT

Recognition proteins could increase cisplatin serStivity

It may be possible to sensitise cells to cisplatin by increasing the concentration of structure-specific recognition proteins which bind to the major cisplatin-DNA adducts, suggest researchers from the Massachusetts Institute of Technology, US. To be clinically significant for the treatment of cisplatin-resistant tumours, such an approach would only need to increase sensitivity by 2- or 3-fold, they say.

These researchers cloned and sequenced a yeast gene, IXR I, encoding the structure-specific recognition protein, Ixrl. This protein was shown to bind specifically to cisplatin-modified DNA, but not to unmodified DNA or DNA modified by an inactive platinum compound.

Further investigation supported the concept that this protein is involved in mediating the cytotoxicity of cisplatin. A mutant yeast strain lacking the IXRI gene was only half as sensitive to the cytotoxicity of cisplatin. This decreased sensitivity correlated with a reduction in the amount of bound cisplatin on DNA in the mutant cells.

The researchers suggest that structure-specific recognition proteins shield DNA-containing intrastrand crosslinks formed by cisplatin from DNA repair enzymes. However, other explanations for the proteins effects are also plausible. Brown Sl. Kellett Pl. Lippard Sl. Ixr I. a yeast protein that binds to platinated DNA and confers sensitivity to cisplatin. Science 261: 603-605. 30 lui 1993 80021.379

ISSN 0156-2703/9310828-0091$1.000 Adla lntern8tlonal Ltd

INPHARMA~28 Aug 1993