Enhanced DNA repair and resistance to cisplatin in human ovarian cancer

Lai, Gi Ming; Ozols, Robert F.; Smyth, John F.; Young, Robert C.; Hamilton, Thomas C.

doi:10.1016/0006-2952(88)90325-5

Cited by 134 publications

(43 citation statements)

References 8 publications

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“…They are multifaceted and complex, and can include the involvement of membrane-associated e ux pumps, the up-regulation of cellular detoxifying thiols, enhanced DNA repair activity and the inhibition of apoptotic pathways (Ishikawa et al, 1994;Andrews et al, 1985;Lai et al, 1988Lai et al, , 1989Chu, 1994;Chu and Chang, 1990;Zhen et al, 1992;Miyake et al, 1998;Citro et al, 1998). In many malignancies, drug resistance is acquired through prolonged and repeated exposure to a chemotherapeutic agent.…”

Section: Discussionmentioning

confidence: 99%

Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications

et al. 2000

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A major obstacle in the systemic treatment of advanced malignant melanoma is its intrinsic resistance to conventionally used chemotherapeutic agents. In order to investigate the mechanisms of this intrinsic resistance, we have previously utilized retroviral insertional mutagenesis on an early-stage, drug sensitive human melanoma cell line (WM35) to establish mutated cell lines that exhibited increased resistance to cis-diamminedichloroplatinum(II) (CDDP). Here, we demonstrate that this increased resistance to CDDP is mediated by the over-expression of tyrosinase-related protein-2 (TYRP2), an enzyme that normally functions in the biosynthesis of the pigment, melanin. Northern and Western blot analyses revealed that the expression of TYRP2 in the virally-derived cell lines as well as in a panel of human melanoma cell lines positively correlated with their levels of resistance to CDDP. Furthermore, enforced expression of TYRP2 in WM35 cells by transfection elevated their resistance to CDDP. The increased CDDP resistance in the virally-derived clones and TYRP2 transfectants was accompanied by a reduction in CDDP-induced apoptosis. Interestingly, the virally-derived CDDP-resistant clones also showed cross resistance to carboplatin and methotrexate, but not taxol, suggesting that TYRP2 over-expression may confer resistance speci®cally to DNA damaging agents.Overall, these results demonstrate a novel mechanism of drug resistance in human melanoma cells that is mediated by the over-expression of TYRP2. Since TYRP2 is expressed only in cells of melanocytic lineage, this may represent the ®rst report of a lineage-speci®c mechanism of drug resistance. In summary, these ®ndings suggest a signi®cant role for TYRP2 in the intrinsic drug resistance phenotype of human melanoma cells and may have important implications in the development of chemosensitization strategies for the clinical management of this disease. Oncogene (2000) 19, 395 ± 402.

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Section: Discussionmentioning

confidence: 99%

Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications

et al. 2000

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“…Most patients with the disease are initially responsive to chemotherapeutic treatment. However, over time, the majority of the patients eventually relapse and become refractory to additional treatment [5]. This drug resistance is one of the major impediments to the successful chemotherapeutic treatment of human malignancies.…”

Section: Introductionmentioning

confidence: 99%

“…However, intensive investigations by many researchers have suggested at least five functional changes that occur in ovarian cancer cells and which could produce resistance to cisplatin: (i) decreased drug accumulation, (ii) increased cellular glutathione, (iii) increased repair capacity to platinum-induced DNA damage at the level of the whole genome and in specific DNA sequences, (iv) altered types of DNA lesions formed by platinum, and (v) altered amounts of platinum DNA damage required to kill resistant cells as compared to sensitive cells [3,4]. Evidence for increased DNA repair capability in cisplatin-resistant ovarian cancer cells has been demonstrated by a number of cellular assays including the measurement of unscheduled DNA synthesis [5], reactivation of cisplatin-damaged plasmid DNA [6], atomic absorption spectroscopy [7], and renaturing agarose gel electrophoresis [8]. Many DNA repair related proteins, such as BRCA1, DNA-PK, and ERCC1, have been shown to be overexpressed in drug-resistant ovarian carcinoma cells [9,10], suggesting enhanced DNA repair activity in these cells.…”

Section: Introductionmentioning

confidence: 99%

Searching for potential biomarkers of cisplatin resistance in human ovarian cancer using a label‐free LC/MS‐based protein quantification method

Fitzpatrick

You²,

Bemis³

et al. 2007

Proteomics Clinical Apps

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Platinum-based chemotherapy, such as cisplatin, is the primary treatment for ovarian cancer. However, drug resistance has become a major impediment to the successful treatment of ovarian cancer. To date, the molecular mechanisms of resistance to platinum-based chemotherapy remain unclear. In this study, we applied an LC/MS-based protein quantification method to examine the global protein expression of two pairs of ovarian cancer cell lines, A2780/A2780-CP (cisplatin-sensitive/cisplatin-resistant) and 2008/2008-C13*5.25 (cisplatin-sensitive/cisplatinresistant). We identified and quantified over 2000 proteins from these cell lines and 760 proteins showed significant expression changes with a false discovery rate of less than 5% between paired groups. Based on the results we obtained, we suggest several potential pathways that may be involved in cisplatin resistance in human ovarian cancer. This study provides not only a new proteomic platform for large-scale quantitative protein analysis, but also important information for discovery of potential biomarkers of cisplatin resistance in ovarian cancer. Furthermore, these results may be clinically relevant for diagnostics, prognostics, and therapeutic improvement for ovarian cancer treatment.

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“…Previous studies indicated that germline cells were hypersensitive to DNA-damaging agents (Cagnoli et al, 1998). Although the mechanisms, of drug resistance are still poorly understood, an increased rate of DNA adduct removal appears to be associated with drug resistance in various human cancers (Lai et al, 1988;Dinapoli et al, 1993;Johnson et al, 1994;Eastman and Schulte, 1998). Drug-resistant human tumours have been shown to express higher levels of nucleotide excision repair (NER) proteins such as XPA, XPB (Lai et al, 1988;Eastman and Schulte, 1998), ERCC1, and cockayne syndrome group B (CSB) (Lai et al, 1988).…”

mentioning

confidence: 99%

“…Although the mechanisms, of drug resistance are still poorly understood, an increased rate of DNA adduct removal appears to be associated with drug resistance in various human cancers (Lai et al, 1988;Dinapoli et al, 1993;Johnson et al, 1994;Eastman and Schulte, 1998). Drug-resistant human tumours have been shown to express higher levels of nucleotide excision repair (NER) proteins such as XPA, XPB (Lai et al, 1988;Eastman and Schulte, 1998), ERCC1, and cockayne syndrome group B (CSB) (Lai et al, 1988). Also, altered expression of genes involved in O-6-alkyltransferasemediated direct DNA repair (O-6-methylguanine DNA methyl transferase, MGMT) or base excision repair pathway also contributes to drug resistance of cancer cells (Chetsanga and Lindahl, 1979;Doetsch and Cunningham, 1990;Cohen et al, 1991;Demple and Harrison, 1994;Gill et al, 1996;Deutsch et al, 1997;Asagoshi et al, 2000;Bielas and Heddle, 2000;Dobson et al, 2000;Evans et al, 2000).…”

mentioning

confidence: 99%

Lack of EGF receptor contributes to drug sensitivity of human germline cells

et al. 2005

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Germline mutations have been associated with generation of various types of tumour. In this study, we investigated genetic alteration of germline tumours that affect the drug sensitivity of cells. Although all germline tumour cells we tested were hypersensitive to DNA-damaging drugs, no significant alteration was observed in their DNA repair activity or the expression of DNA repair proteins. In contrast, germline tumours expressed very low level of epidermal growth factor receptor (EGFR) compared to drug-resistant ovarian cancer cells. An immunohistochemical analysis indicated that most of the primary germline tumours we tested expressed very low level of EGFR. In accordance with this, overexpression of EGFR in germline tumour cells showed an increase in drug resistance, suggesting that a lack of EGFR, at least in part, contributes to the drug sensitivity of germline tumours.

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Enhanced DNA repair and resistance to cisplatin in human ovarian cancer

Cited by 134 publications

References 8 publications

Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications

Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications

Searching for potential biomarkers of cisplatin resistance in human ovarian cancer using a label‐free LC/MS‐based protein quantification method

Lack of EGF receptor contributes to drug sensitivity of human germline cells

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