Article thumbnail
Location of Repository

Clinical resistance to platinum chemotherapy in ovarian cancer

By C. Newton

Abstract

Platinum drugs are the most active agents in ovarian cancer. Their cytotoxicty results from DNA crosslinking. High tumour response rates are seen, but 80 % of patients relapse. Major mechanisms of platinum resistance in patients remain to be established. We have studied DNA interstrand crosslinking and its repair in response to ex vivo treatment with cisplatin in forty patients with ovarian cancer using the single cell gel electrophoresis (comet) assay. Tumour cells from resected tumours or tumour and mesothelial cells from ascites were obtained from chemonaïve patients and those relapsing after platinum-based therapy. The average percent decrease in tail moment at the peak of crosslinking was 61.1% {\pm9.25} in 34 pre-chemotherapy patient samples following treatment with {100\mu}M cisplatin. In 14 post-chemotherapy patient samples it was 58.1% {\pm9.94}. The average percentage repair at 24 hours was 3.6% {\pm18.89} in prechemotherapy patients and 44.6% {\pm43.4} for post-chemotherapy patients (p<0.001). In 6 paired samples, before and after chemotherapy the average percentage repair at 24 hours was 7.2% {\pm12.64} increasing to 69.5% {\pm23.42} after chemotherapy. Differences in cell cycling, and cell signalling gene expression levels using microarray analysis was found, between pre- and post-chemotherapy patients. Real time PCR was also used to investigate the levels of ERCC1 (excision-related cross complementation group 1) in 3 of these paired patient samples, which was found to be increased by an average of 14.4% +/-0.8% in 3 post-chemotherapy samples. In ten pre-chemotherapy and seven post-chemotherapy patient tumours incubated ex vivo with {50\mu}M melphalan, the percent decrease in tail moment at the peak of crosslinking was 41.4 {\pm11.2}, and 44.6 {\pm7.6}, respectively. 24 hours later the percentage repair was 3.1 {\pm25.6} for untreated and 2.8 {\pm26.3} for treated tumours. In conclusion, repair of DNA interstrand crosslinks appears to be an important mechanism of clinical platinum resistance in ovarian cancer. Repair of melphalan crosslinks is unaffected

Publisher: UCL (University College London)
Year: 2009
OAI identifier: oai:eprints.ucl.ac.uk.OAI2:15840
Provided by: UCL Discovery

Suggested articles

Citations

  1. (2002). 53BPI, a mediator of the DNA damage checkpoint.
  2. (2001). A change in microsatelite instability caused by cisplatin-based chemotherapy of ovarian cancer.
  3. (2000). A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.
  4. (1996). A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation.
  5. (1979). A mathematical model for relating the drug sensitivity of tumours to their spontaneous mutation rate.
  6. (2002). A phase II trial of ZD0473 in platinum-pretreated ovarian cancer.
  7. (2000). A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.
  8. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
  9. (2004). Accessed December 18 th,
  10. (2000). Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins.
  11. (1991). Acquired cispaltin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatinDNA lesions and reduced drug accumulation.
  12. (2005). Activation of PI3K/Akt pathway by PTEN reduction and PI3KCA mRNA amplification contributes to cisplatin resistance in ovarian cell line.
  13. (1985). Adducts of the antitumour drug cis –diamminedichloroplatinum(II) with DNA: Formation, identification and quantitation.
  14. (1991). Advanced Ovarian Cancer Trialists Group.
  15. (2005). Advances in the management of epithelial ovarian cancer.
  16. (2000). Akt and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumour growth.
  17. (2003). AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance.
  18. (2002). Alkylating agents from Souhami R.L, Tannock I, Hohenberger and Horiot J-C. Oxford textbook of oncology, second edition.
  19. (1997). Analysis of expression of cMOAT(MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines.
  20. (2001). Analysis of gene expression profiles associated with cisplatin resistance in human ovarian cancer cell lines and tissues using cDNA microarray.
  21. (1999). Antagonism of p53-dependent apoptosis by mitogen signals.
  22. (2004). Anthracyclines: molecular advances and pharmacologic evelopments in antitumour activity and cardiotoxicity.
  23. (2008). Ascites from epithelial ovarian cacner contain high levels of functional decoy receptor-3 (DcR-3) and is associated with platinum resistance.
  24. (1992). Association between GTPase activators for Rho and Ras families.
  25. (2008). Associations between p53 overexpression and multiple measures of clinical outcome in high-risk, early stage or suboptimally resected, advanced stage epithelial ovarian cancers: A Gynecologic Oncology Group study.
  26. (2004). Atlas of Genetics and Cytogenetics in Oncology and Haematology. http://www.infobiogen.fr/services/chromcancer/Tumors/OvarianTumOverviewID5231.htm l Accessed
  27. (2001). ATM phosphorylates histone H2AX in response to DNA double-strand breaks.
  28. (1998). ATP-dependent interaction of human mismatch repair proteins and dual role of PCNA
  29. (2000). BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.
  30. (2003). Binding discrimination of MutS to a set of lesions and compound lesions (base damage and mismatch) reveals its potential role as a cisplatin-damaged DNA sensing protein.
  31. (1993). Biochemistry of mutidrug resistance mediated by the multidrug transporter.
  32. (2004). Bioconductor: open software development for computational biology and bioinformatics.
  33. (2000). BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells.
  34. (2000). BRCA1 facilitates stree-induced apoptosis in breast and ovarian caner cell lines.
  35. (2003). BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis.
  36. (2002). BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair.
  37. (2002). BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
  38. (2002). BRCA1 transactivates the cyclin-dependent kinase inhibitor p27 (kip1).
  39. (1998). BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II).
  40. (2001). BRCA2 is required for homologydirected repair of chromosomal breaks.
  41. (2004). break repair.
  42. (2003). Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
  43. (2003). Breast and ovarian cancer.
  44. (1999). Cancer cell cycle control.
  45. (1995). Cell Biological marker of drug resistance in ovarian carcinoma.
  46. (2001). cell cycle arrest in response to antimicrotubule agents.
  47. (2004). Cell Grading and Differentiation www.baymoon.com/~gyncancer/library/weekly Accessed December 18th,
  48. (2002). Cellular and molecular pharmacology of oxaloplatin
  49. (1994). Cellular pharmacology of dichloro(thylenediamine)platinum(II) in cispaltin sensitive and resistant human ovarian carcinoma cells.
  50. (1999). Characterisation of the repeat-tract instability and mutator phenotypes conferred by a Tn3 insertion in RFC1, the large subunit of the yeast clamploader.
  51. (1987). Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues.
  52. (1998). Characterization of vincristine transport by the Mr 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione.
  53. (1998). Chemotherapy in advanced ovarian cancer: four systematic meta-analysis of individual patient data from 37 randomised trials. Advanced Ovarian Cancer Trialists Group.
  54. (1999). chromatin disruption and modification.
  55. (1973). Cis-dichlorodiammineplatinum (NSC119875): a phase I study.
  56. (1979). Cis-dichlorodiammineplatinum(II) for the treatment of advanced ovarian cancer.
  57. (2002). Cisplatin and analogues from Souhami R.L, Tannock I, Hohenberger and Horiot J-C. Oxford textbook of oncology, second edition,
  58. (1998). Cisplatin induction of ERCC1 mRNA expression in A2780/CP70 human ovarian cancer cells.
  59. (1993). Cisplatin sensitivity/resistance in UV repair-deficient Chinese hamster ovary cells of complementation groups
  60. (1995). Cisplatin- and carboplatin-DNA adducts: is PT-AG the cytotoxic lesion?
  61. (1998). Cisplatin- and paclitaxelinduced apoptosis of ovarian carcinoma cells and the relationship between bax and bak upregulation and the functional status of p53.
  62. (1997). Clinical pharmacokinetics and dose optimization of carboplatin.
  63. (2002). Collaberative Ovarian Neoplasm Group.
  64. (1990). Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards.
  65. (2000). Computer based analyses of the 5’-flanking regions of selected genes involved in the nucleotide excision repair complex.
  66. (1997). Controlling the false discovery rate: a practical and powerful approach to multiple testing.
  67. (2000). Coupled homologous and nonhomologous repair of double-strand breaks preserves genomic integrity in mammalian cells.
  68. (1991). Cross-sensitivity of gamma-ray-sensitive hamster mutants to cross-linking agents.
  69. (1996). Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomised trial in patients with suboptimal stage
  70. (2004). Cystic adenomatoid tumour of the mediastinum.
  71. (2000). Damage recognition in nucleotide excision repair of DNA.
  72. (2004). Defective removal of DNA crosslinks in a repair deficient mutant of Chinese hamster cells.
  73. (1999). Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours.
  74. (2002). Defects in interstrand cross-link uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin.
  75. (1996). Defining progression of ovarian carcinoma during follow-up according to Ca 125: a North Thames Ovary Group Study.
  76. (2004). Dependence of the cytotoxicity of DNAdamaging agents on the mismatch repair status of human cells.
  77. (2000). Dial 9-1-1 for p53:mechanisms of p53 activation by cellular stress.
  78. (1997). Disruption of mouse ERCC1 results in novel repair syndrome with growth failure, nuclear abnormalities and senescence.
  79. (1998). Dissociation of cytokine-induced phosphorylation of bad and activation of PKB/akt: involvement of MEK upstream of bad phosphorylation.
  80. (2003). Divide and conquer:nucleotide excision repair battles cancer and ageing
  81. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139.
  82. (2007). DNA Microarrays: a Powerful Genomic Tool for Biomedical and Clinical Research.
  83. (1999). DNA recombination: the replication connection.
  84. (2006). DNA repair by ERCC1 in nonsmall-cell lung cancer and cisplatin-based adjuvant chemotherapy.
  85. (2000). DNA replication is required to elicit cellular responses to psoralen-induced DNA interstrand crosslinks.
  86. (1996). DNA topoisomerases.
  87. (2002). Dominant-negative activity of a BRCA1 truncation mutant:effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line.
  88. (1997). Double strand break repair.
  89. (2006). DoxorubicinDNA adducts induce a form of non-topoisomerase II- mediated form of cell death.
  90. (2001). Drug resistance reversal –are we getting closer?
  91. (1999). Drug resistance-associated markers Pglycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma.
  92. (1998). Effect of interleukin-1 alpha and tumour necrosis factor-alpha on cisplatin-induced ERCC1 mRNA expression in a human ovarian carcinoma cell line.
  93. (2000). Effect of p53 status on sensitivity to platinum complexes in a human ovarian cacner cell line.
  94. (2003). Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in human ovarian cancer cell lines.
  95. (2001). Enhanced expression and activity of DNA polymerase beta in human ovarian tumour cells:impact on sensitivity towards antitumour agents.
  96. (2006). Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy.
  97. (1999). Eukaryotic DNA mismatch repair.
  98. (2003). Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen.
  99. (2004). Excision repair cross complementing group-1: gene expression and platinum resistance.
  100. (1986). Experimental chemotherapy and concepts related to the cell cycle.
  101. (2003). Exploration, normalization, and summaries of high density oligonucleotide array probe level data.
  102. (2005). Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease.
  103. (2004). Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA1 gene.
  104. (1998). Expression of the p53 tumour suppressor gene as a prognostic marker in platinum-treated patients with ovarian cancer.
  105. (1999). Fas ligand-induced apoptosis.
  106. (2003). First Line treatment regimens and the role of consolidation therapy in advanced ovarian cancer.
  107. (2001). FLICE-inhibitory proteins:regulators of death receptor-mediated apoptosis.
  108. (2000). Formation of nuclear bax/p53 complexes is associated with chemotherapy induced apoptosis.
  109. (1998). Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines.
  110. (2001). Functions of BRCA1 and BRCA2 in the biological response to DNA damage.
  111. (2005). GAPs in growth factor signalling.
  112. (1988). GC-rich regions in genomes as targets for DNA alkylation.
  113. (2003). Gemcitabine: current role and future options in the treatment of ovarian cancer.
  114. (2005). Gene Expression Profiles Predict Early Relapse in Ovarian Cancer after Platinum-Paclitaxel Chemotherapy.
  115. (2000). General and Systematic Pathology, 3 rd edn. Churchill and Livingstone
  116. (2001). genome maintenance mechanisms for preventing cancer.
  117. (1996). Glutathione and drug resistance.
  118. (1993). Glutathione S-transferase expression in benign and malignant ovarian tumours.
  119. (1993). Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukaemia cells. Molecular characterization of glutathione-platinum complex and its biological significance.
  120. (2000). Going APE over ref-1.
  121. (2000). Guanylyl cyclases and signaling by cyclic GMP.
  122. (2006). Gynaecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer.
  123. (1999). Histone acetylases and deacetylases in cell proliferation.
  124. (2001). Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol,
  125. (1997). hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents.
  126. (2002). Human exonuclease I is required for 5' and 3' mismatch repair.
  127. (1996). Human RAD51 protein promotes ATPdependent homologous pairing and strand transfer reaction in vitro.
  128. (2002). IAP proteins: blocking the road to death’s door.
  129. (1997). Identification and characterisation of XPA-binding domain of hHR23B.
  130. (1995). Identification of mismatch repair genes and thei role in the developement of cancer.
  131. (1988). Increased DNA repair as a mechanism of acquired resistance to cisdiamminedichloroplatinum(II) in human ovarian cancer cell lines.
  132. (1992). Increased gene-specific repair of cisplatin interstrand crosslinks in cisplatinresistant human ovarian cancer cell lines.
  133. (2000). Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells. Role of ercc1-xpf.
  134. (1990). Increased removal of DNA-bound platinum in a human ovarian cancer cell line resistant to cis-diamminedichloroplatinum(II).
  135. (1999). Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.
  136. (2000). Influence of the proto-oncogene c-fos on cisplatin sensitivity.
  137. (2001). Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway.
  138. (2004). Inhibition of JNK reduces G2/M transit independent p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells.
  139. (1999). Inhibition of the jun kinase pathway blocks DNA repair, enhances p53-mediated apoptosis and promotes gene amplification.
  140. (1999). Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular to DNA damage.
  141. (2004). Intermediate-dose melphalan with stem cell support in platinum refractory ovarian cancer.
  142. (1973). International Histological classification of Tumours: No. 9. Histological Typing of Ovarian Tumours. Geneva World Health Organisation.
  143. (2002). Irinotecan: mechanisms of tumour resistance and novel strategies for modulating its activity.
  144. (1993). Kinetic analysis of the reaction of melphalan with water, phosphate and glutathione. Drug Metab.
  145. (2001). Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC1 expression.
  146. (2004). Linear models and empirical bayes method for assessing differential expression in microarray experiments.
  147. (2004). Linear models and empirical Bayes methods for assessing differential expression in microarray experiments.
  148. (2003). MCD1 is required for the intra-S-phase DNA damage checkpoint.
  149. (1999). Measurement of DNA cross-linking in patients on ifosfomide therapy using the single cell gel electrophoresis (comet) assay.
  150. (2001). Mechanisms of p53-dependent apoptosis.
  151. (2000). MEK/ERK signalling pathway regulates the expression of bcl-2, bcl –XL, and Mcl-1 and promotes survival of human pancreatic cancer cells.
  152. (1991). Melphalan, Therapeutic drugs 2,
  153. (2004). Mismatch repair and DNA damage signalling.
  154. (2005). Modifications of DNA by platinum complexes: Relation to resistance of tumours to platinum antitumour drugs. Drug resistance updates
  155. (2002). Modulation of cytostatic efficacy of melphalan by glutathione:mechanisms and efficacy.
  156. (1995). Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas.
  157. (2001). Molecular mechanisms controlling the cell cycle: fundamental aspects and implicatins for oncology.
  158. (2002). Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications.
  159. (1981). Molecular mechanisms of crosslinking of alkylating agents and platinum complexes. Molecular actions and targets for cancer chemotherapeutic agents Academic,
  160. (2005). Molecular mechanisms of drug resistance.
  161. (1994). mRNA levels of XPAC and ERCC1 in ovarian tumour tissue correlates with response to platinum containing chemotherapy.
  162. (2002). Multidrug resistance in cancer: role of ATP-dependent transporters.
  163. (2000). Multiple pathways of recombination define cellular responses to cisplatin.
  164. (1999). Multiple pathways of recombination induced by doublestrand breaks in saccharomyces cerevisiae.
  165. (2007). Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth.
  166. (1998). Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinaemia II/Dubin-Johnson syndrome.
  167. (2006). MZF1 possesses a repressively regulatory function in ERCC1 expression.
  168. (1996). Nature Rev Mol cell Biol 3, 401-410.Sancar A.
  169. (2006). NCI issues clinical announcement for preferred method of treatment for advanced ovarian cancer [http://www.nih.gov/news/pr/jan2006/nci-04.htm] (accessed 21
  170. (2008). NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumours to cisplatin by depletion of cellular thiols.
  171. (2000). New guidelines to evaluate the response to treatment in solid tumours.
  172. (2003). Nucleotide excision repair from site-specifically platinum-modified nucleosomes.
  173. (1998). Nuclesosome unfolding during DNA repair in normal and xeroderma pigmentosum (group C) human cells.
  174. (2004). Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinumbased anticancer agents.
  175. (2003). Oral melphalan as a treatment for platinum-resistant ovarian cancer.
  176. (2001). Ovarian cancer, Fallopian tube Carcinoma and Peritoneal Carcinoma: Cancer principles and Practice of Oncology, 6 th edn.
  177. (1998). Ovarian cancer. Onkologi, Liber,
  178. (1999). p53 and chemosensitivity.
  179. (1997). p53, the cellular gatekeeper for growth and division.
  180. (2006). Pegylated liposomal doxorubicin consolidation therapy after platinum/paclitaxel-based chemotherapy for suboptimally debulked, advanced-stage epithelial ovarian cancer patients.
  181. (2006). pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line subsequent treatment of advanced ovarian cacner: a systematic review and economic evaluation.
  182. (2001). Peptide transport by the multidrug resistance protein MRP1.
  183. (1995). Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals.
  184. (1997). Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of p-glycoprotein.
  185. (1998). Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.
  186. (1991). Phosphorylation of c-jun mediated by MAP kinases.
  187. (2003). Physical and functional interaction between DNA ligase IIIalpha and poly(ADP-Ribose) polymerase 1 in DNA single-strand break repair.
  188. (2009). PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther. 17, 8(1) Epub ahead of print.
  189. (2004). Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro.
  190. (2000). Prevention of cisplatin-DNA adduct repair and potentiation of cisplatin-induced apoptosis in ovarian carcinoma cells by proteasome inhibitors.
  191. (1998). Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynaecologic Oncology Group study.
  192. (2001). Prolonged wild-type p53 protein accumulation and cisplatin resistance.
  193. (1979). Promotion of microtubule assembly in vitro by Taxol.
  194. (2005). protection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells.
  195. (1995). Purification and characterization of the XPF-ERCC1 complex of human DNA repair excision nuclease.
  196. (2006). Rad54: the swiss army knife of homologous recombination.
  197. (2000). Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three year results.
  198. (2006). Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGOOVAR and GINECO.
  199. (1997). Rapid deubiquitination of nucleosomal histones in human tumour cells caused by proteasome inhibitors and stress response inducers: Effects on replication, transcription, translation and the cellular stress response.
  200. (1995). rd edn. Churchill Livingstone.
  201. (1995). Reaction mechanism of human DNA repair excision nuclease.
  202. (2005). Reduced membrane protein associated withresistance of human squamous carcinoma cells to methotrexate and cisplatin.
  203. (1996). Repair of cisplatin-DNA adducts by the mammalian excision nuclease.
  204. (2001). Repair of DNA double-strand breaks.
  205. (2002). Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma.
  206. (2001). Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance.
  207. (2000). Repair of intermediate structures produced at DNA interstrand crosslinks in Saccharomyces cerevisiae.
  208. (2002). Repair of oxidative damage: assessing its contribution to cancer prevention.Mutagenesis
  209. (1996). Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis.
  210. (1999). Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks.
  211. (2003). Resistance to chemotherapy in advanced ovarian cancer: mechanisms and current strategies.
  212. (2004). Resistance to chemotherapy-induced apoptosis via decreased caspase-3 activity and overexpression of antiapoptotic proteins in ovarian cancer.
  213. (2004). Response of combination platinum and gemcitabine chemotherapy for recurrent epithelial ovarian carcinoma.Gynecology
  214. (2000). Reversal of drug resistance in human tumour xenografts by 2’-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter.
  215. (2003). Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1.
  216. (1993). Role of carrier ligand in platinum resistance of human carcinoma cell lines.
  217. (1992). Role of chemotherapy in the future treatment of ovarian cancer.
  218. (2000). Role of nucleotide escision repair gene ERCC1 in formation of recombination-dependent rearrangemtns in mammalian cells.
  219. (2004). Role of the transcription factor Ets-1 in cisplatin resistance.
  220. (2006). Selectivity and potency of cyclindependent kinase inhibitors. The aaps journal
  221. (2002). Sensing and repairing DNA double-strand breaks.
  222. (2003). Sensing DNA damage through ATRIP recognition of RPAssDNA complexes.
  223. (2003). Sensitization to the cytotoxicity of cisplatin by transfection with nucleotide excision repair gene xeroderma pigmentosum group a antisense RNA in human lung adenocarcinoma cells.
  224. (1996). Sequentioal binding of DNA repair proteins RPA and ERCC1 to XPA in vitro.
  225. (2006). Should patients with ovarian cancer receive intraperitoneal chemotherapy following initial cytoreductive surgery?
  226. (1999). Significance of multi-drug-resistant proteins in predicting chemotherapy response and prognosis in epithelial ovarian cancer.
  227. (1977). Sites in nucleic acids reacting with alkylating agents of differing carcinogenicity or mutagenicity.
  228. (2005). Specific killing of BRCA2 deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
  229. (2003). Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein.
  230. (1998). Stable interaction between the products of the BRCA1 and BRCA2 tumour suppressor genes in mitotic and meiotic cells.
  231. (2000). Surfing the p53 network.
  232. (2002). Survival and longer-term toxicity results of the SCOTROC study: docetaxel-carboplatin (DC) vs paclitaxel-carboplatin (PC) in epithelial ovarian cancer (EOC).
  233. (2001). Synergistic induction of apoptosis by the combination of trail and and chemotherapy in chemoresistant ovarian cancer cells.Gynaecol
  234. (2000). The biochemistry of apoptosis.
  235. (2003). The coordinated functions of the E.coli MutS and MutL proteins in mismatch repair.
  236. (2004). The DNA bouble-strand break response pathway:becoming more BRCAish than ever.
  237. (1987). The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes.
  238. (1997). The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin.
  239. (2004). The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells.
  240. (2002). The relationship between the roles of BRCA genes in DNA repair and cancer predisposition.
  241. (2004). The role of BRCA1 in the cellular response to chemotherapy.
  242. (2007). The role of glutathione-S-transferase polymorphisma in ovarian cancer survival.
  243. (1998). The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance:correlation with replicative bypass of platinum-DNA adducts.
  244. (1996). Three distinct signalling responses by murine fibroblasts to genotoxic stress.
  245. (1988). Topoisomerases in human disease.
  246. (1998). Topotecan for the treatment of advanced epithelial ovarian cancer: an open label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel.
  247. (2002). Transcription-coupled nucleotide excision repair as a determinant of cispplatin sensitivity of human cells.
  248. (2008). Treatment of recurrent or persistent platinum-refractory ovarian, fallopian tube or primary peritoneal cancer with gemcitabine and topotecan A phase II trial of the Puget Sound Oncology Consortium. Gynecol Oncol (epub ahead of print).
  249. (1994). Tumour suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo.
  250. (1993). Update on malignant ovarian germ cell tumours.
  251. (2004). Use of Ca-125 in clinical trial evaluation of new therapeutic drugs for ovarian cancer.
  252. (2003). Use of Ca-125 to assess response to new agents in ovarian cancer trials.
  253. (2001). Use of Ca125 to define progression of ovarian cancer in patients with persistently elevated levels. J clin Oncol.
  254. (1995). Value of P-glycoprotein, glutathion Stransferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas.
  255. (2004). www.cancerresearchuk.org/aboutcancer/specificcancers/ovariancancer Accessed December 18th, 2004Cancer Research UK. Ovarian Cancer. Statistics and Prognosis. www.cancerhelp.org.uk Accessed
  256. (2000). Xeroderma pigmentosum group C protein complex is the initiator of global genomic nucleotide excision repair.
  257. (2003). XIAP regulates Akt activity and caspase-3-dependent cleavage during cispplatin-induced apoptotsis in human ovarian epithelial cancer cells.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.