Cancer Letters

Cancer Letters

Volume 346, Issue 2, 1 May 2014, Pages 163-171
Cancer Letters

Mini-review
Nucleotide excision repair: Why is it not used to predict response to platinum-based chemotherapy?

https://doi.org/10.1016/j.canlet.2014.01.005Get rights and content

Abstract

Platinum based therapy is one of the most effectively used chemotherapeutic treatments for cancer. The mechanism of action of platinum compounds is to damage DNA and drive cells into apoptosis. The most commonly used platinum containing agents are cis-diammine-dichloroplatinum (II)], more commonly known as cisplatin, its analogue carboplatin, and oxaliplatin. Cisplatin is used to treat a wide variety of tumours such as ovarian, testicular, head and neck and non-small cell lung cancers (NSCLCs). In addition, it forms the basis of most combined treatment regimes. Despite this, cisplatin and its analogues are extremely toxic and although some patients benefit substantially from treatment, a large proportion suffer the toxic side effects without any therapeutic benefit. Nucleotide excision repair (NER) is a versatile DNA repair system that recognises DNA damage induced by platinum based therapy. For many years the components of the NER pathway have been studied to determine mRNA and protein expression levels in response or resistance to cisplatin in many forms of cancer; particularly testicular, ovarian and NSCLCs. Despite the consistent finding that over or under expression of subsets of NER proteins and mRNA highly correlate with response to cisplatin, the translation of these findings into the clinical setting has not been forthcoming. This review summarises the results of previous investigations into NER in cisplatin response and clinical trials where the expression of NER proteins were compared to the response to platinum therapies in treatment.

Introduction

Platinum based therapy is one of the most effectively used chemotherapeutic treatments for cancer. The mechanism of action of platinum compounds is to damage DNA, primarily by formation of monoadducts followed by intra and inter-strand crosslinks, which consequently distort the DNA helix, inhibit DNA replication and drive cells into apoptosis [1], [2], [3], [4]. The first discovered and most commonly used platinum containing agent is cis-diammine-dichloroplatinum (II)], more commonly known as cisplatin [5]. Cisplatin and its analogue, carboplatin form the same platinum–DNA intrastrand crosslinks. The final platinum compound commonly used is oxaliplatin, which produces a slightly different form of intrastrand cross-link, which may account in part for its different spectrum of activity. Cisplatin is commonly used to treat a wide variety of tumours such as ovarian, testicular, head and neck and NSCLCs [1]. In addition, it is often called the scaffolding of chemotherapy as it forms the basis of most combined treatment regimes. The downside to cisplatin and its analogues is that they are extremely toxic and although some patients benefit substantially from treatment, a large proportion suffer the toxic side effects without any therapeutic benefit [6].

Testicular and ovarian tumours have a very high response rate to platinum therapies, but various other forms of solid tumours such as lung, colorectal, breast and skin cancers have a high level of resistance. Tumour resistance to platinum therapies can occur by 3 different mechanisms: Loss of apoptotic signalling after damage has occurred; DNA repair/removal of the damage or tolerance of the damage [7]. The hypersensitivity of testicular cancer to cisplatin appears to be due to DNA-repair deficiency [8]. Additionally, cisplatin-resistant ovarian cell lines have been shown to have increased DNA-repair capacity, indicated by the number of DNA adducts present compared to the cisplatin-sensitive parental cell line [9]. Lung cancer cell lines also have increased DNA-repair capacity when cisplatin resistant.

In early clinical studies investigating the role of DNA repair in cisplatin resistance, elevated DNA repair capacity (DRC) was associated with resistance to cisplatin in lung cancer cell lines [10]. DRC is a direct measurement of the repair capability of cells after treatment with a DNA damaging agent or after transfection with a reporter plasmid that has undergone DNA damage. A recent study has shown DRC in peripheral lymphocytes from patients with NSCLCs treated with first-line platinum-based therapies was an independent predictor of survival [11].

Cross-links between guanine bases are induced by cisplatin, carboplatin and oxaliplatin (Fig. 1). Cisplatin and carboplatin cause the same cross-link but oxaliplatin causes a structurally distinct adduct containing a bulky 1,2-diaminocyclohexane group [12]. The damage caused by all these platinum compounds is helix distorting, therefore it is recognised and repaired by the distinct DNA repair pathway known as nucleotide excision repair (reviewed in [13]). The first reports that NER is involved in the repair of cisplatin-induced DNA damage was in the late 1980s, when Hansson and colleagues confirmed involvement of several NER proteins [14], [15]. Since then studies have investigated the mRNA and protein expression levels and genetic variation in almost every component of the NER pathway in relation to cisplatin response and resistance.

Section snippets

Nucleotide excision repair (NER)

NER is a versatile DNA repair system that eradicates a range of lesions that all have one commonality: distortion of the helical structure of DNA. The majority of insults that result in DNA distorting lesions are persistently present in our daily lives. For example: in food (e.g. nitrosamines), the air (e.g. benzo[a]pyrenes from cigarette smoke) and the environment (e.g. cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6–4) pyrimidine photoproducts (6–4PPs) from sunlight) [16], [17], [18].

Global genome repair

GGR is responsible for recognising helix-distorting DNA damage on the non-transcribed strand of actively transcribed genes and inert non-coding regions of the genome. It is particularly important for detecting replication forks blocked by DNA damage which result in mutations and chromosomal aberrations [34]. GGR is comprised of several proteins that work in concert to detect DNA damage and initiate the remainder of the NER pathway. XPC initially recognises the damage [35], then the damaged DNA

XPD (ERCC2)

XPD is 5′-3′ helicase which is a structural component of the TFIIH complex responsible for DNA unwinding surrounding a lesion after damage recognition via GGR or TCR [21]. XPD and ERCC1 have strongly correlated mRNA expression which, in the wake of the discovery that ERCC1 expression can predict cisplatin response, has led to many studies focusing on XPD in cisplatin resistance. Weaver and colleagues [51] identified a strong correlation (R2 = 0.82, p = 0.0001) between XPD mRNA expression and

ERCC1

Of all the NER related proteins, ERCC1 has received the most attention over recent years in relation to platinum drug resistance. It was first discovered in the 1990s to be more predictive of response to cisplatin than most of the other NER proteins [63], [75]. ERCC1 forms a heterodimer with XPF which is responsible for incision of the damaged DNA strand 5′ of the lesion (reviewed in [2]). In vitro studies have shown that downregulation or double knockdown of the XPF-ERCC1 complex enhances

Future considerations

The major limitation preventing NER being further investigated in cisplatin response is the inconsistent results due to differing assays and tissue types in previous studies. Both Western blot and IHC analysis of protein levels rely heavily on the quality of antibodies and usually only a present/absent designation can be made. Real-time PCR quantification of mRNA is much more accurate as the commercially available fluorescent probes are very specific and easily quantified. The relationship

Conclusion

Over the last 2 decades a myriad of studies have investigated the mRNA and/or protein expression levels of every member of the NER pathway in response to cisplatin. There is overwhelming evidence that there is clinical utility in using mRNA or protein levels of NER to predict response to cisplatin treatment and potentially in determining resistance in real-time. The translation of the large body of scientific data into the clinical setting has not yet occurred but there is huge potential for

Conflict of interest

The author declares no conflicts of interest.

Acknowledgements

The author would like to acknowledge the funding support of the Australian National Health & Medical Research Council (NH&MRC). The NH&MRC had no involvement in the preparation or submission of this article.

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