Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic changes underlying the development of resistance to the platinum-containing drugs are poorly defined. We analyzed six resistant cell lines using comparative genomic hybridization (CGH) in order to screen and identify possible genetic changes in common. We compared parental 2008 and A2780 human ovarian cancer cells to sublines selected for resistance to cisplatin (DDP) (2008/C8, 2008/C13*5.25, 2008/A, A2780/CP); we also compared 2008 cells to sublines selected for resistance to antimonite (2008/H) and arsenite (2008/I) which demonstrated cross-resistance to DDP. DNA samples from the resistant cell lines were hybridized against DNA from the parental cells rather than from normal human cells to permit detection of only those changes associated with the development of resistance. The DNA sequence copy number changes were surprisingly numerous in the DDP, antimony, and arsenite-resistant variants of the 2008 cell line and most of the chromosomes were affected. On the other hand, in the A2780/CP subline only a few changes were found and these were limited to just four chromosomes. The most common findings among the DDP-resistant cell lines were gains of material from chromosomes or chromosome arms 2q (5 out of 6 lines), 4 (4/6), 6q (5/6), and 8q (4/6). Deletions were observed on chromosomes or chromosome arms 2p (4/6), X (4/6), 7p (5/6), 11p (4/6), and 13 (4/6). The most frequently involved chromosomal regions, affected in the majority of cell lines, were: gain of 2q14.1-q33, 4p15.2-p13, 4q22-q25, 4q31.1-q34, 6q13-q16, 8q12-q21.2, and loss of Xp22.2-q21, 7p21-p14, 11cen-p14 in sublines of 2008, and loss of 2pter-p22 and 13q21 in sublines of 2008 and A2780. The results suggest that the acquired resistance and cross-resistance to DDP in these cell lines was associated with substantial genomic instability, quite unlike the changes observed in association with the development of resistance to drugs participating in the multidrug resistance phenotype.
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PMID:Comparative genomic hybridization analysis of chromosomal changes occurring during development of acquired resistance to cisplatin in human ovarian carcinoma cells. 908 68

Nine human ovarian cancer cell lines that express wild-type (wt) or mutated (mut) p53 were used to evaluate the cytotoxicity induced by cisplatin (DDP). The concentrations inhibiting the growth by 50% (IC50) were calculated for each cell line, and no differences were found between cells expressing wt p53 and mut p53. Using, for each cell line, the DDP IC50, we found that these concentrations were able to induce an increase in p53 levels in all four wt-p53-expressing cell lines and in one out of five mut-p53-expressing cell lines. WAF1 and GADD45 mRNAs were also increased by DDP treatment, independently of the presence of a wt p53. Bax levels were only marginally affected by DDP, and this was observed in both wt-p53- and mut-p53-expressing cells. DDP-induced apoptosis was evident 72 h after treatment, and the percentage of cells undergoing apoptosis was slightly higher for wt-p53-expressing cells. However, at doses near the IC50, the percentage of apoptotic cells was less than 20% in all the cell lines investigated. We conclude that the presence of wt p53 is not a determinant for the cytotoxicity induced by DDP in human ovarian cancer cell lines.
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PMID:DDP-induced cytotoxicity is not influenced by p53 in nine human ovarian cancer cell lines with different p53 status. 927 24

The interaction of cisplatin [cis-diamminedichloroplatinum (II), or DDP] with calf thymus DNA has previously been shown to result in the generation of superoxide anions (O2-) and hydroxyl radicals (OH) in a cell-free system. The effect of hyperthermia (42 degrees C) on the generation of such active oxygen radicals was examined by chemiluminescence of a Cypridina luciferin analog (CLA) with DNA extracted from a human ovarian cancer cell line (A2780). Hyperthermia significantly increased chemiluminescence of CLA (CCLA) 1.17- to 1.51-fold at DDP concentrations of 10 to 40 uM, relative to values at 37 degrees C. The extent of DDP-induced CCLA correlated significantly (r = 0.973) with that of DDP cytotoxicity in A2780 cells. These results suggest that hyperthermic enhancement of DDP-induced generation of active oxygen radicals contributes to the hyperthermic potentiation of DDP cytotoxicity.
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PMID:Hyperthermic enhancement of cisplatin-induced generation of active oxygen radicals in a cell-free system. 967 58

Thioredoxin (TRX) is a widely distributed Mr 13,000 protein with a redox-active dithiol/disulfide in the active site. The TRX system, consisting of TRX, TRX reductase, and NADPH, has an intracellular reducing capacity. Another reducing capacity, glutathione (GSH), can be associated with cis-diaminedichloroplatinum (cDDP) resistance. Therefore, we examined the involvement of TRX in cDDP resistance using two cell lines designated St/DDP and HT/DDP, which were established from the human gastric cancer cell line St-4 and the colon cancer cell line HT-29. St/DDP and HT/DDP were seven and five times as resistant to cDDP as their parental lines, and the expression of TRX in these variants was increased by 2.5- and 2-fold, respectively. The expression of TRX in the complete revertant cells of St/DDP was reduced as low as that in St-4 cells. TRX reductase activity was also increased in St/DDP and HT/DDP, suggesting that activation of the TRX system was associated with in vitro-acquired cDDP resistance. Because cDDP is the first-line drug against ovarian cancer, we examined the expression of TRX in 11 human ovarian cancer cell lines not treated with cDDP in vitro. Positive correlation between TRX expression and cDDP resistance was observed in these cell lines (r = 0.76, P = 0.007). This correlation was comparable to that between GSH content and cDDP resistance (r = 0.69, P = 0.019). These results suggest a possible involvement of TRX, as well as GSH, in cDDP resistance.
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PMID:Increased expression of thioredoxin/adult T-cell leukemia-derived factor in cisplatin-resistant human cancer cell lines. 981 87

Growth factors have been demonstrated to regulate the proliferation and viability of a number of cell lineages. Because most drugs used in chemotherapy kill cells through programmed cell death, by the process of apoptosis, we determined whether growth factors, specifically epidermal growth factor (EGF) and lysophosphatidic acid (LPA), which we have demonstrated recently to be a potent growth factor for ovarian cancer cells, would alter the ability of cis-diamminedichloroplatinum (cis-DDP), the most effective chemotherapeutic agent for ovarian cancer, to kill the HEY ovarian cancer cell line. We demonstrate that both EGF and LPA decrease the ability of cis-DDP to kill HEY ovarian cancer cells as assessed by colony-forming cell activity and dye reduction. Morphological changes, DNA release, and electron microscopy suggested that LPA and EGF protect ovarian cancer cells from programmed cell death induced by cis-DDP. Because LPA is present in high levels in ascitic fluid from ovarian cancer patients, and the EGF receptor is expressed by tumor cells from a significant portion of patients where it correlates with prognosis, growth factor modulation of cis-DDP-induced apoptosis may play a role in the poor prognosis associated with ovarian cancer.
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PMID:Peptide and lipid growth factors decrease cis-diamminedichloroplatinum-induced cell death in human ovarian cancer cells. 981 1

Forty-three patients with ovarian cancer were entered on this trial and treated with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following iv hydration, the cisplatin was administered through an intraperitoneal catheter in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for overall and progression-free survival with a median follow-up of 70 months (range: 3-162 months); 39 patients are evaluable for response. All complete responses were surgically confirmed. The median age was 59 (range 28-82 years); 3 patients were stage IC, 5 were IIC, 14 patients were stage III (optimally debulked), 14 patients were stage III (suboptimally debulked), and 7 patients were stage IV. Two patients had received prior alkylator therapy. Six of 8 patients with Stage IC or II remain without evidence of disease at a mean of 12 years following chemotherapy. Of 14 optimally debulked stage III patients, there were 7 complete responses, 3 partial responses, 1 patient with stable disease, and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there were 4 complete responses, 4 partial responses, 3 with stable disease, 2 progressions on treatment, and 1 inevaluable patient. Five-year progression-free and overall survivals for stage III optimally debulked patients are 21 and 64%, respectively. At 10 years, progression-free and overall survivals for this group are 21 and 29%, respectively. Toxicity included neutropenia (complicated by sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three patients developed transient serum creatinine elevations >2.0 mg/dl; however, decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses which required a cisplatin dose reduction per protocol. Controllable hypomagnesemia, nausea, and emesis were also observed. We conclude that the combination of iv CA and ip DDP is an effective regimen with long-term progression-free and overall survivals that compare favorably with those of other published studies of intravenous or intraperitoneal chemotherapy. This report is unusual in terms of the prolonged follow-up for all patients enrolled. These long-term results lend further support to recently published trials documenting the efficacy of intraperitoneal chemotherapy for patients with this disease.
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PMID:Phase II trial of intraperitoneal cisplatin with intravenous doxorubicin and cyclophosphamide in previously untreated patients with advanced ovarian cancer-long-term follow-up. 1060 Mar

By exposing Igrov-1 human ovarian cancer cells to increasing concentrations of Ecteinascidin-743 (ET-743), either for a short or prolonged time, we obtained sublines resistant to ET-743 which overexpress Pgp. The most resistant clone (Igrov-1/25 ET) was evaluated for biological and pharmacological characterizations. The increased Pgp levels of Igrov-1/25 ET were not due to amplification of the mdr-1 gene but to increased mRNA levels. No increase in other multidrug resistance-related proteins such as MRP or LRP was observed in Igrov-1/25 ET. The IC50 values of ET-743 against Igrov-1/25 ET was approximately 50 times higher than the parental cell line. Resistance was not reversed while maintaining the cell line in drug-free medium for at least 24 months. Igrov-1/25 ET was cross-resistant to Doxorubicin and VP16 while it was equally sensitive to L-PAM, MNNG, CPT and only marginally less sensitive to Cis-DDP and Oxaliplatin compared to the parental cell line. Igrov-1/25 ET exposed to Doxorubicin retained this drug much less, mainly because of a more efficient drug efflux. The cyclosporine analogue SDZ PSC-833 reversed the resistance of Igrov-1/25 ET to ET-743, without any enhancement of the drug activity against the parental Igrov-1 cell line. Igrov-1/25 ET exhibits typical features of cell lines overexpressing the mdr-1 gene and can be a potentially useful tool in selecting ET-743 non-cross-resistant analogues as well as to investigate methods to counteract resistance to this drug.
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PMID:Isolation and characterization of an IGROV-1 human ovarian cancer cell line made resistant to Ecteinascidin-743 (ET-743). 1081 11

We examined the consequences of p73alpha overexpression on gene expression and cellular response to anticancer agents in clones from the human ovarian cancer cell line A2780. Using microarray filters, the expression of 588 genes in two clones overexpressing p73alpha (A2780/p73.4 and A2780/ p73.5) in comparison with empty vector-transfected cells was evaluated. There were clear differences in gene expression profiles. Both of the clones showed a marked increase in the expression of genes involved in DNA repair, including genes participating in nucleotide excision repair and mismatch repair. This was confirmed by reverse transcription-PCR and Northern blot analysis and was associated with an increase in the ability of p73alpha-expressing clones to repair two different DDP (cis-dichlorodiammine platinum)-damaged plasmids in a host reactivation assay. p73alpha overexpressing clones were less sensitive than parental cells to alkylating agents treatment or UV radiation but equally sensitive to the topoisomerase I inhibitor topotecan, which indicated that the increase in expression of DNA repair genes has implications for the response to DNA damaging agents.
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PMID:P73a overexpression is associated with resistance to treatment with DNA-damaging agents in a human ovarian cancer cell line. 1122 86

Superoxide anions (O2-) generated by cisplatin [cis-diamminedichloroplatinum (II), DDP] were determined by measuring the chemiluminescence from the luminescence probe, 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (methyl Cypridina luciferin analog, MCLA), in monolayer cultures of a human ovarian cancer cell line (A2780) in physiological saline at pH 7.0. In a time-course study, chemiluminescence of MCLA (C-MCLA) showed a peak level at 10 min and a background level at 60 min after the addition of DDP. The intensity of C-MCLA increased with increasing concentrations of DDP or MCLA in a limited concentration range, and was significantly correlated (r = 0.960) with the number of A2780 cells. DDP-induced C-MCLA was completely inhibited by the addition of the O2- scavenger, superoxide dismutase (SOD). However, SOD did not decrease DDP cytotoxicity in terms of clonogenic cell survival. These findings suggest that DDP generates extracellular O2-, probably by interaction with the cellular membrane in A2780 cells, and O2- does not lead to cellular damage.
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PMID:Detection and cytotoxicity of cisplatin-induced superoxide anion in monolayer cultures of a human ovarian cancer cell line. 1126 42

Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs may overcome the intrinsic and / or acquired resistance of cancer cells to DDP, we investigated the effect of a combination of DDP with paclitaxel and a combination of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsically resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations showed additive to synergistic antitumor activity. A time-dependent platinum (Pt) accumulation was observed in the DDP-sensitive KF cell line, while a decrease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines by exposure to paclitaxel or SN-38. Ouabain, a Na(+),K(+)-ATPase inhibitor, decreased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxel- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP), which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DDP alone. These results suggest that paclitaxel and SN-38 overcome DDP resistance of ovarian cell lines by controlling intracellular accumulation of DDP via both the influx and efflux systems.
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PMID:Paclitaxel and SN-38 overcome cisplatin resistance of ovarian cancer cell lines by down-regulating the influx and efflux system of cisplatin. 1171 50


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