Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours

Metastatic cancer in adults usually has a fatal outcome. In contrast, advan ced testicular germ cell tumours are cured in over 80% of patients using ci splatin based combination chemotherapy [1]. An understanding of why these c ells are sensitive to chemotherapeutic drugs is likely to have implications for the treatment of other types of cancer. Earlier measurements indicate that testis tumour cells are hypersensitive to cisplatin and have a low cap acity to remove cisplatin-induced DNA damage from the genome [2,3]. We have investigated the nucleotide excision repair (NER) capacity of extracts fro m the well-defined 833K and GCT27 human testis tumour cell lines. Both had a reduced ability to carry out the incision steps of NER in comparison with extracts from known repair-proficient cells. Immunoblotting revealed that the testis tumour cells had normal amounts of most NER proteins, but low le vels of the xeroderma pigmentosum group A protein (XPA) and the ERCC1-XPF e ndonuclease complex. Addition of XPA specifically conferred full NER capaci ty on the testis tumour extracts. These results show that a low XPA level i n the testis tumour cell lines is sufficient to explain their poor ability to remove cisplatin adducts from DNA and might be a major reason for the hi gh cisplatin sensitivity of testis tumours. Targeted inhibition of XPA coul d sensitise other types of cells and tumours to cisplatin and broaden the u sefulness of this chemotherapeutic agent. (C) Elsevier Science Ltd ISSN 096 0-9822.