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【科普】DNA修复和肺癌生存---古罗马的两面神
Adi F. Gazdar, M.D.
Volume 356:771-773 February 22, 2007 Number 8
全文链接：http://content.nejm.org/cgi/content/full/356/8/771
Lung cancer, the most common cause of cancer deaths globally, results in about 1 million deaths each year. Despite advances in treatment over the past two decades, the improvement in long-term survival has been limited: only about 15% of patients survive for 5 years or longer. The high mortality is due mainly to early and widespread dissemination of the cancer, which means that surgical removal of early-stage non–small-cell lung cancer results in the best chance for long-term survival. Chemotherapy for advanced non–small-cell lung cancer (which accounts for about 85% of all lung cancers) or as adjuvant treatment for patients with resected tumors offers modest benefits in improved quality of life and increased survival times.
Currently, the usual chemotherapy regimen combines a platinum-containing drug with another cytotoxic agent. However, platinum-based therapies have drawbacks: severe toxic effects for the patient and drug resistance in the tumor cell. Markers that predict which patients with resected early-stage cancers will survive longest without additional therapy and markers that predict resistance to conventional chemotherapy would be of considerable clinical benefit. The article by Zheng and colleagues in this issue of the Journal (pages 800–808) suggests that these two crucial but very different needs may both be filled by a single pair of markers.
Platinum compounds exert their cytotoxic effects by binding covalently to genomic DNA, forming adducts that result in altered forms of DNA. Such couplings activate DNA-repair processes, and unless these adducts are repaired before the DNA replicates, they may lead to nucleotide substitutions, deletions, and chromosome rearrangements (mutagenesis) or to activation of cell-signaling pathways that result in cell death (apoptosis). The three widely used platinum compounds — cisplatin, carboplatin, and oxaliplatin — damage tumors through apoptosis mediated by the activation of the death receptor and mitochondrial pathways.
A number of endogenous and environmental agents cause genomic damage that, unless corrected, lead to cell death or mutations. In turn, these results contribute to aging and carcinogenesis. There are multiple cellular mechanisms for correcting or repairing incorrect, damaged, or broken DNA sequences, but in mammalian cells, nucleotide excision repair is the major pathway for removing damaged bases, including bulky, helix-distorting adducts, from DNA. Much of our knowledge of the nucleotide excision repair process (see diagram) comes from studies of xeroderma pigmentosum, in which inherited mutations of certain crucial nucleotide excision repair genes disable the repair of DNA damage from ultraviolet light, a defect that results in multiple skin cancers of various types in skin that has been exposed to the sun.1
Figure 1
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The Life and Death of a Cisplatin Adduct.
In Panel A, a cisplatin molecule binds covalently to genomic DNA, forming a bulky, helix-distorting adduct. The most prevalent adduct is the intrastrand linkage of two adjacent guanine bases by the nitrogen atoms at position 7 (the GG adduct). In chemosensitive cells with low nucleotide excision repair activity, apoptosis usually follows. In chemoresistant cells with high nucleotide excision repair activity, the adduct may be excised and the DNA repaired. First, the adduct is recognized, and proteins of the nucleotide excision repair complex are assembled at the adduct site (Panel . The heterodimeric protein excision repair cross-complementation group 1 (ERCC1)–XPF is the last component to be assembled — the rate-limiting step. Unwinding of the DNA duplex in the immediate vicinity of the adduct results in the formation of a bubble. Next, endonucleases create dual incisions flanking the damaged bases (Panel C), with the protein XPG acting on the 3' side and the heterodimer ERCC1–XPF acting on the 5' side. The segment of about 22 to 32 nucleotides containing the adduct is removed. Then, the excised segment is repaired by polymerases and the accessory replication proteins PCNA, RPA, and RFC (Panel D). The integrity of the damaged strand is restored by DNA ligase. The protein ribonucleotide reductase M1 (RRM1), although not an integral part of the repair complex, catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides, providing the building blocks for reconstitution of the excised oligonucleotide. The repair process is complete (Panel E), and the original state of the DNA is restored. (Modified from Friedberg.1)
It has been known for about a decade that nucleotide excision repair is involved in the resistance of several types of tumors to certain drugs, including platinum compounds. In 2006, Olaussen et al. reported that the absence of immunohistochemical evidence of the excision repair cross-complementation group 1 (ERCC1) protein in tumors was associated with a survival benefit from cisplatin-based adjuvant chemotherapy for resected non–small-cell lung cancer.2 ERCC1 is a highly conserved protein that is essential for life. Although it is only one of several proteins involved in nucleotide excision repair, it plays a rate-limiting role. It forms a complex with another protein, XPF, and the heterodimer performs the last of the initial steps of nucleotide excision repair — excision of the DNA strand on the 5' side of the DNA damage site (see diagram). The expression of ERCC1 is influenced by complex factors, including polymorphisms and alternative splicing.
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作者:admin@医学,生命科学 2011-05-07 17:11
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