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1.
Low levels of human copper transporter 1 (hCtr1) mRNA are associated with a shorter progression-free survival after platinum-based therapy. Pretreatment with a copper-lowering agent such as trientine enhanced hCtr1-mediated platinum uptake. Therefore, we conducted a pilot study (NCT01178112) of carboplatin and trientine with the goal of resensitizing patients with advanced cancer to platinum chemotherapy. This case report reviews the outcomes of 5 patients with platinum-resistant high-grade epithelial ovarian cancer enrolled on the study to date. Overall, they tolerated treatment well. Severe adverse events that occurred in 2 patients were myelosuppression, notably anemia requiring transfusion. Dose-limiting toxicity was not observed within the first 28 days (cycle 1). After 2 cycles of therapy, partial remission was achieved in 1 patient (10+ months), stable disease in 3 patients (2, 3.5+, and 5 months, respectively), and 1 patient had progressive disease. These cases provide preliminary clinical evidence that the role of decreasing copper levels in reversing platinum resistance merits additional clinical investigation. Evaluation of this novel strategy is warranted in larger studies to assess the efficacy of this approach for treating platinum-resistant advanced epithelial ovarian cancer in patients with high copper levels. 相似文献
2.
Yonezawa A Masuda S Yokoo S Katsura T Inui K 《The Journal of pharmacology and experimental therapeutics》2006,319(2):879-886
We have examined the role of the human organic cation transporters [hOCTs and human novel organic cation transporter (hOCTN); SLC22A1-5] and apical multidrug and toxin extrusion (hMATE) in the cellular accumulation and cytotoxicity of platinum agents using the human embryonic kidney (HEK) 293 cells transiently transfected with the transporter cDNAs. Both the cytotoxicity and accumulation of cisplatin were enhanced by the expression of hOCT2 and weakly by hOCT1, and those of oxaliplatin were also enhanced by the expression of hOCT2 and weakly by hOCT3. The hOCT-mediated uptake of tetraethylammonium (TEA) was markedly decreased in the presence of cisplatin in a concentration-dependent manner. However, oxaliplatin showed almost no influence on the TEA uptakes in the HEK293 cells expressing hOCT1, hOCT2, and hOCT3. The hMATE1 and hMATE2-K, but not hOCTN1 and OCTN2, mediated the cellular accumulation of cisplatin and oxaliplatin without a marked release of lactate dehydrogenase. Oxaliplatin, but not cisplatin, markedly decreased the hMATE2-K-mediated TEA uptake. However, the inhibitory effect of cisplatin and oxaliplatin against the hMATE1-mediated TEA uptake was similar. The release of lactate dehydrogenase and the cellular accumulation of carboplatin and nedaplatin were not found in the HEK293 cells transiently expressing these seven organic cation transporters. These results indicate that cisplatin is a relatively good substrate of hOCT1, hOCT2, and hMATE1, and oxaliplatin is of hOCT2, hOCT3, hMATE1, and hMATE2-K. These transporters could play predominant roles in the tissue distribution and anticancer effects and/or adverse effects of platinum agent-based chemotherapy. 相似文献
3.
Cycloplatam (CP), a new antitumor platinum compound of the second generation, was first synthesized in Russia. This drug shows less toxicity in vivo than the widely used cisplatin and carboplatin and a higher antitumor activity than carboplatin. CP is not nephrotoxic with respect to the platinum-based antitumor agents. CP is actually studied in clinical phase II trials in Russia and Armenia. Promising results were obtained in patients with lung, ovary, and prostate cancers. The aim of this work was to study the micronuclei (MN) inducing effect of CP in vivo in murine bone marrow cells and in human lymphocytes in vitro. The mutagenic activity of CP in bone marrow of mice was significantly lower than that of cisplatin at equitoxic doses. In human lymphocytes CP induced a dose-dependent increase of MN, beginning at a very low dose (0.1 micro M). Our results showed that CP is much less toxic and MN inducing in vivo in murine bone marrow than cisplatin. In vitro data evidenced that CP is more toxic and genotoxic to human cells than cisplatin. The evidence of a MN-induced activity of an antitumor drug suggests a potential risk for long-time survivors. 相似文献
4.
Theile D Detering JC Herold-Mende C Dyckhoff G Haefeli WE Weiss J Burhenne J 《The Journal of pharmacology and experimental therapeutics》2012,341(1):51-58
Cisplatin (diaminodichloroplatinum) is the favored platinum (Pt) drug for the treatment of head and neck squamous cell carcinoma (HNSCC). However, Pt drug alternatives such as carboplatin (diaminoplatinum-cyclobutan-1,1-dicarboxylate) or oxaliplatin [oxalato[(1R,2R)-cyclohexanediamino]platinum] have not been comprehensively investigated in HNSCC. Moreover, little data reveal the decisive efficacy determinant and whether Pt drug efficacy is truly concentration-dependent. Using five human HNSCC cell lines, we determined the concentrations of cisplatin, carboplatin, and oxaliplatin leading to 50% inhibition of cell proliferation (IC(50)). Concurrently we quantified cellular drug uptake by liquid chromatography coupled to tandem mass spectrometry and evaluated mRNA expression of drug transporters involved in Pt drug uptake by quantitative real-time polymerase chain reaction. Mean IC(50) among the five cell lines was 6.2 ± 1.9 μM for cisplatin and 11.6 ± 4.2 μM for oxaliplatin, whereas carboplatin showed significantly lower proliferation inhibition (IC(50) 107.5 ± 21.2 μM). In agreement with this finding carboplatin poorly accumulated in HNSCC cells, compared with cisplatin and oxaliplatin. HNSCC cell lines expressed Pt drug transporters. Taken together, the results demonstrate: 1) carboplatin was less effective and was poorly taken up; 2) a high individuality among cell lines was found concerning the accumulation of cisplatin and oxaliplatin despite similar in vitro efficacy; and 3) distinct expression of SLC22A2 and ABCC2 accompanies strong uptake and cytotoxicity of Pt drugs. In conclusion, we demonstrate that in vitro efficacy of cisplatin and oxaliplatin in HNSCC is concentration-independent because they exhibited different uptake characteristics but similar efficacies, suggesting oxaliplatin as a promising alternative against HNSCC that needs further evaluation in clinical trials. 相似文献
5.
Lovejoy KS Serova M Bieche I Emami S D'Incalci M Broggini M Erba E Gespach C Cvitkovic E Faivre S Raymond E Lippard SJ 《Molecular cancer therapeutics》2011,10(9):1709-1719
Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC(50) = 171-443 μmol/L), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 hours (IC(50) = 24 μmol/L). Pyriplatin caused a G(2)-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin-DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use. 相似文献
6.
Nassini R Gees M Harrison S De Siena G Materazzi S Moretto N Failli P Preti D Marchetti N Cavazzini A Mancini F Pedretti P Nilius B Patacchini R Geppetti P 《Pain》2011,152(7):1621-1631
Platinum-based anticancer drugs cause neurotoxicity. In particular, oxaliplatin produces early-developing, painful, and cold-exacerbated paresthesias. However, the mechanism underlying these bothersome and dose-limiting adverse effects is unknown. We hypothesized that the transient receptor potential ankyrin 1 (TRPA1), a cation channel activated by oxidative stress and cold temperature, contributes to mechanical and cold hypersensitivity caused by oxaliplatin and cisplatin. Oxaliplatin and cisplatin evoked glutathione-sensitive relaxation, mediated by TRPA1 stimulation and the release of calcitonin gene-related peptide from sensory nerve terminals in isolated guinea pig pulmonary arteries. No calcium response was observed in cultured mouse dorsal root ganglion neurons or in naïve Chinese hamster ovary (CHO) cells exposed to oxaliplatin or cisplatin. However, oxaliplatin, and with lower potency, cisplatin, evoked a glutathione-sensitive calcium response in CHO cells expressing mouse TRPA1. One single administration of oxaliplatin produced mechanical and cold hyperalgesia in rats, an effect selectively abated by the TRPA1 antagonist HC-030031. Oxaliplatin administration caused mechanical and cold allodynia in mice. Both responses were absent in TRPA1-deficient mice. Administration of cisplatin evoked mechanical allodynia, an effect that was reduced in TRPA1-deficient mice. TRPA1 is therefore required for oxaliplatin-evoked mechanical and cold hypersensitivity, and contributes to cisplatin-evoked mechanical allodynia. Channel activation is most likely caused by glutathione-sensitive molecules, including reactive oxygen species and their byproducts, which are generated after tissue exposure to platinum-based drugs from cells surrounding nociceptive nerve terminals. 相似文献
7.
Hagrman D Goodisman J Souid AK 《The Journal of pharmacology and experimental therapeutics》2004,308(2):658-666
The binding of platinum (Pt) drugs (oxaliplatin, carboplatin, and cisplatin) to glutathione (GSH, 6.75 mM) was investigated at 37 degrees C in Hepes (100 mM, pH approximately 7.4) or Tris-NO(3) (60 mM, pH 7.4) buffer and NaCl (4.62, 6.63, or 7.82 mM). The conditions were chosen to mimic passage of clinical concentrations of the drugs (135 microM) through the cytosol. The reactions were monitored by UV-absorption spectroscopy, high-performance liquid chromatography (HPLC), and atomic absorption spectroscopy. The initial rates, detected by UV absorbance, were similar for oxaliplatin and cisplatin reacting with GSH and were more than 5-fold faster than for carboplatin reacting with GSH. The Pt contents in HPLC eluates corresponding to unbound drug decreased exponentially with time, confirming that the reactions were first order in [Pt drug] and allowing determination of the pseudo first-order rate constants (k(1)). The second-order rate constants (k(2)) were calculated as k(1) divided by [GSH]. The k(2) value for oxaliplatin reacting with GSH was approximately 3.8 x 10(-2) M(-1) s(-1), for cisplatin reacting with GSH approximately 2.7 x 10(-2) M(-1) s(-1), and for carboplatin reacting with GSH approximately 1.2 x 10(-3) M(-1) s(-1) (approximately 32-fold slower than that of oxaliplatin and approximately 23-fold slower than that of cisplatin). These results demonstrate an influence of ligands surrounding the Pt coordination sphere on the reactivity of Pt(2+) with GSH. 相似文献
8.
A. du Bois Werner Vach Clemens Siebert Rolf Holy Michael Ledergerber Ulrike Wechsel Hanna Kriesinger-Schroeder 《Supportive care in cancer》1997,5(3):212-218
Evaluation of the relationship between parameters of serotonin (5-HT) metabolism and emesis in platinum-based chemotherapy.
Female patients receiving chemotherapies containing either cisplatin (35 patients; 80 courses) or carboplatin (65 patients;
102 courses) were recruited. Recording of emesis and measurements of urinary 5-hydroxyindoleacetic acid (5-HIAA), the main
metabolite of 5-HT, was performed over 3 days. Comparisons were performed for single-agent cisplatin (DDP) versus single-agent
carboplatin (CBDCA), single-agent high-dose DDP (≥75 mg/m2) versus high-dose DDP combined with cyclophosphamide, high-dose versus low-dose DDP (≤50 mg/m2), and single-agent CBDCA versus a combination with alkylating agents. Cisplatin induced both a significantly higher frequency
of emesis and a significantly higher increase of 5-HIAA excretion than carboplatin. The velocity of 5-HIAA increase may correlate
better with emetogenic potential than peak 5-HIAA excretion levels. The increase of 5-HIAA excretion induced by cisplatin
was limited to day 1. Higher cisplatin doses showed both a higher emetogenic potential and a more pronounced increase in urinary
5-HIAA on day 1. No significant difference was found when single-agent cisplatin was compared with cisplatin combined with
cyclophosphamide. In contrast, a combination of carboplatin with alkylating agents induced a larger increase in urinary 5-HIAA
and showed a higher emetogenic potential than single-agent carboplatin. Low-dose cisplatin induced less emesis than carboplatin
combination therapy, but induced a larger increase in urinary 5-HIAA. Our findings provide evidence for a relationship between
emetogenic potential and patterns of 5-HIAA excretion following platinum-based chemotherapy. 相似文献
9.
BACKGROUND: Oxaliplatin is one of the platinum chemotherapeutics that includes cisplatin and carboplatin. Antibodies to all three drugs have caused immune hemolytic anemia (IHA). In an investigation of oxaliplatin‐induced IHA, the negative plasma control agglutinated oxaliplatin‐coated red blood cells (RBCs). Previous preparations of this control had not agglutinated oxaliplatin‐ or cisplatin‐coated RBCs. STUDY DESIGN AND METHODS: Drug‐coated RBCs, prepared by incubating 1/10th volume of RBCs with 1 mg/mL drug in phosphate‐buffered saline for 1 hour at 37°C, were incubated with plasma from random blood donors and patients. Plasma was treated with dithiothreitol to determine the immunoglobulin class. Hapten inhibition was performed by incubating plasma with solutions of oxaliplatin or cisplatin. RESULTS: Nineteen of 121 (16%) donors' plasma samples agglutinated oxaliplatin‐coated RBCs; 7 of 102 (7%) donors' plasma samples agglutinated cisplatin‐coated RBCs. Two of 50 (4%) patients' samples agglutinated oxaliplatin‐coated RBCs. The agglutinin was immunoglobulin M and inhibited by oxaliplatin and cisplatin. CONCLUSION: An agglutinin reactive with oxaliplatin‐coated RBCs was found in 16% of donors' and 4% of patients' samples. Inhibition by oxaliplatin and cisplatin indicates the antibody may be directed to platinum. The presence of this antibody in healthy individuals may be related to the increasing environmental presence of platinum in air and soil as a byproduct of automobile catalytic converters and pharmaceuticals in our water and food chain. This antibody in individuals without IHA suggests that testing untreated and enzyme‐treated RBCs in the presence of a solution of drug may be the best method to investigate IHA caused by drugs in the platinum family. 相似文献
10.
BACKGROUND: Two patients were suspected of having immune hemolytic anemia (IHA) due to oxaliplatin. A related drug, cisplatin, is known to cause nonimmunologic protein adsorption (NIPA). Studies were performed to determine the presence of oxaliplatin-dependent antibodies in addition to oxaliplatin-induced NIPA.
STUDY DESIGN AND METHODS: Sera and eluates from the two patients were tested against red blood cells (RBCs) treated with oxaliplatin, cisplatin, and carboplatin (another platinum drug). Sera were also tested against untreated RBCs in the presence of the same drugs. Testing with pooled normal sera and anti-human albumin was used to demonstrate the presence of NIPA. Oxaliplatin-treated RBCs sensitized with the patients' sera and pooled normal sera were tested by a monocyte monolayer assay (MMA) to determine potential clinical significance.
RESULTS: Both patients had high-titer antibodies to oxaliplatin in their sera that reacted with oxaliplatin-treated RBCs and with untreated RBCs in the presence of oxaliplatin. RBCs treated with oxaliplatin, cisplatin, and carboplatin all demonstrated NIPA (pooled normal sera and anti-human albumin were reactive to low titers). NIPA was also detected in tests with untreated RBCs in the presence of oxaliplatin and cisplatin. Lower-titer reactivity of both patients' sera with cisplatin may have been due to NIPA and/or cross-reactivity of anti-oxaliplatin with cisplatin. MMAs were weakly positive due to NIPA and more strongly positive due to oxaliplatin antibodies.
CONCLUSION: Two patients with IHA were demonstrated to have oxaliplatin-dependent antibodies. Oxaliplatin was also shown to cause NIPA. The drug-dependent antibody and/or the drug-induced NIPA could have contributed to the patients' hemolytic anemia. 相似文献
STUDY DESIGN AND METHODS: Sera and eluates from the two patients were tested against red blood cells (RBCs) treated with oxaliplatin, cisplatin, and carboplatin (another platinum drug). Sera were also tested against untreated RBCs in the presence of the same drugs. Testing with pooled normal sera and anti-human albumin was used to demonstrate the presence of NIPA. Oxaliplatin-treated RBCs sensitized with the patients' sera and pooled normal sera were tested by a monocyte monolayer assay (MMA) to determine potential clinical significance.
RESULTS: Both patients had high-titer antibodies to oxaliplatin in their sera that reacted with oxaliplatin-treated RBCs and with untreated RBCs in the presence of oxaliplatin. RBCs treated with oxaliplatin, cisplatin, and carboplatin all demonstrated NIPA (pooled normal sera and anti-human albumin were reactive to low titers). NIPA was also detected in tests with untreated RBCs in the presence of oxaliplatin and cisplatin. Lower-titer reactivity of both patients' sera with cisplatin may have been due to NIPA and/or cross-reactivity of anti-oxaliplatin with cisplatin. MMAs were weakly positive due to NIPA and more strongly positive due to oxaliplatin antibodies.
CONCLUSION: Two patients with IHA were demonstrated to have oxaliplatin-dependent antibodies. Oxaliplatin was also shown to cause NIPA. The drug-dependent antibody and/or the drug-induced NIPA could have contributed to the patients' hemolytic anemia. 相似文献
11.
Masahede Noji Ryoichi Kizu Yasutaka Takeda Nachio Akiyama Iwao Yoshizaki Masazumi Eriguchi Yoshinori Kidani 《Biomedicine & Pharmacotherapy》2005,59(5):224-229
A new dinuclear docking Pt(II) complex, (cis-diammine) (l-1,2-cyclohexanediamine)(mu-dichloro)-diplatinum(II) oxalate was synthesized by reacting oxaliplatin(l-OHP, [Pt(oxalato)(L-dach)]), L-dach = 1R, 2R-cyclohexanediamine), with cisplatin (CDDP). Elemental analysis of the compound indicated that it was 1:1 molar ratio complex of oxaliplatin and cisplatin. A plausible chemical structure has been proposed as Cl(-) bridged dinuclear complex, judged from its yellow coloration and NMR spectral analysis. This complex can be denoted as, i.e. [Pt(2)Cl(2)(NH(3))(2)(L-dach)](COO)(2) (L-OHP/CDDP). The complex showed higher cytotoxicity against L1210 than the parent complexes and low cross-resistance against L1210/CDDP and L1210/DACH. Its antitumor activity was also tested in vivo against murine leukemia L1210 cell lines. The complex showed much higher activity than the mixture(1:1 molar ratio) of oxaliplatin and cisplatin. The antitumor effect against L1210/CDDP was very high, showing collateral sensitivity, being similar to that of oxaliplatin, and against L1210/DACH it showed no cross-resistance. 相似文献
12.
Irinotecan has recently been found to be one of the most active agents in the treatment of small-cell lung cancer (SCLC). Japanese investigators have led the way in the early investigation of irinotecan, and multiple studies are now ongoing in the United States. In a phase II trial conducted by the West Japan Thoracic Oncology Group, irinotecan was associated with a median survival of 13 months in patients with extensive-stage disease. Subsequently, the Japanese Clinical Oncology Group completed a phase III trial comparing irinotecan plus cisplatin to cisplatin and etoposide. In this study, median, 1-year, and 2-year survival rates were superior with irinotecan and cisplatin. Two confirmatory phase III trials are in progress in the United States. Based on these early data, it is likely that irinotecan and a platinum agent will prove to be at least as effective as any other treatment for patients with extensive-stage SCLC. Investigators have embarked on combining irinotecan with carboplatin in anticipation that this will be a preferable treatment. Phase I/II trials are complete and the doses and schedules have been recommended. As a result, we are currently exploring irinotecan and carboplatin in phase II trials in both extensive- and limited-stage settings. In addition, several of the newer biologic targeted agents are being tested in SCLC in combination with newer chemotherapy regimens. The results from these trials are eagerly awaited. 相似文献
13.
Bauer JA Trask DK Kumar B Los G Castro J Lee JS Chen J Wang S Bradford CR Carey TE 《Molecular cancer therapeutics》2005,4(7):1096-1104
Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumors that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 overexpression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines overexpress p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-x(L) expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-x(L) expression in these cells. We tested a small-molecule BH3 mimetic, (-)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-x(L), for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (-)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-x(L) for survival and BH3 mimetic agents, such as (-)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC. 相似文献
14.
姜黄素增强卵巢癌耐药细胞株COC1/DDP对顺铂敏感性的研究 总被引:1,自引:2,他引:1
目的:探讨姜黄素的使用与卵巢癌顺铂耐药细胞株COC1/DDP对顺铂化疗敏感性的关系。方法:采用MTT法和TUNEL法检测姜黄素、顺铂单独和联合作用时对COC1/DDP细胞增殖和凋亡的影响;RT-PCR检测上述各组细胞凋亡相关基因Bcl-2、Smac的表达。结果:顺铂的浓度在1.25~5μg/mL时与姜黄素合用后耐药细胞生存率下降明显(P<0.05),尤以2.5μg/mL顺铂和20μmol/L姜黄素联合作用时,耐药细胞生存率下降最明显;顺铂与姜黄素联合用药与单独用药相比,凋亡率明显增加(P<0.05);联合用药与单独用药相比Bcl-2 mRNA的表达明显降低(P<0.05),Smac mRNA的表达明显增高(P<0.05)。结论:姜黄素能够显著抑制COC1/DDP增殖,并能增强该细胞系对顺铂的敏感性,机制可能与降低Bcl-2基因的表达,增加Smac基因的表达有关。 相似文献
15.
The purpose of this study was to evaluate the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in vitro and in vivo, examine the role of KIT in small cell lung cancer (SCLC), and anticipate clinical utility of SU11248 in SCLC. SU11248 is an oral, multitargeted tyrosine kinase inhibitor with direct antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, KIT, and FLT3 receptors. Treatment of the KIT-expressing SCLC-derived NCI-H526 cell line in vitro with SU11248 resulted in dose-dependent inhibition of stem cell factor-stimulated KIT phosphotyrosine levels and proliferation. The biological significance of KIT inhibition was evaluated in vivo by treating mice bearing s.c. NCI-H526 tumors with SU11248 or another structurally unrelated KIT inhibitor, STI571 (Gleevec), which is also known to inhibit Bcr-Abl and PDGFRbeta. SU11248 treatment resulted in significant tumor growth inhibition, whereas inhibition from STI571 treatment was less dramatic. Both compounds reduced phospho-KIT levels in NCI-H526 tumors, with a greater reduction by SU11248, correlating with efficacy. Likewise, phospho-PDGFRbeta levels contributed by tumor stroma and with known involvement in angiogenesis were strongly inhibited by SU11248 and less so by STI571. Because platinum-based chemotherapy is part of the standard of care for SCLC, SU11248 was combined with cisplatin, and significant tumor growth delay was measured compared with either agent alone. These results expand the profile of SU11248 as a KIT signaling inhibitor and suggest that SU11248 may have clinical potential in the treatment of SCLC via direct antitumor activity mediated via KIT as well as tumor angiogenesis via vascular endothelial growth factor receptor FLK1/KDR and PDGFRbeta. 相似文献
16.
Wangpaichitr M Sullivan EJ Theodoropoulos G Wu C You M Feun LG Lampidis TJ Kuo MT Savaraj N 《Molecular cancer therapeutics》2012,11(3):604-615
Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatin-resistant tumors have higher reactive oxygen species (ROS) levels and can be exploited for targeted therapy. Here, we show that increased secretion of the antioxidant thioredoxin-1 (TRX1) resulted in lowered intracellular TRX1 and contributed to higher ROS in cisplatin-resistant tumors in vivo and in vitro. By reconstituting TRX1 protein in cisplatin-resistant cells, we increased sensitivity to cisplatin but decreased sensitivity to elesclomol (ROS inducer). Conversely, decreased TRX1 protein in parental cells reduced the sensitivity to cisplatin but increased sensitivity to elesclomol. Cisplatin-resistant cells had increased endogenous oxygen consumption and mitochondrial activity but decreased lactic acid production. They also exhibited higher levels of argininosuccinate synthetase (ASS) and fumarase mRNA, which contributed to oxidative metabolism (OXMET) when compared with parental cells. Restoring intracellular TRX1 protein in cisplatin-resistant cells resulted in lowering ASS and fumarase mRNAs, which in turn sensitized them to arginine deprivation. Interestingly, cisplatin-resistant cells also had significantly higher basal levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Overexpressing TRX1 lowered ACC and FAS proteins expressions in cisplatin-resistant cells. Chemical inhibition and short interfering RNA of ACC resulted in significant cell death in cisplatin-resistant compared with parental cells. Conversely, TRX1 overexpressed cisplatin-resistant cells resisted 5-(tetradecyloxy)-2-furoic acid (TOFA)-induced death. Collectively, lowering TRX1 expression through increased secretion leads cisplatin-resistant cells to higher ROS production and increased dependency on OXMET. These changes raise an intriguing therapeutic potential for future therapy in cisplatin-resistant lung cancer. 相似文献
17.
Raymond E Faivre S Chaney S Woynarowski J Cvitkovic E 《Molecular cancer therapeutics》2002,1(3):227-235
Oxaliplatin, a diaminocyclohexane-containing platinum, has a spectrum of activity and mechanisms of action and resistance that appear to be different from those of other platinum-containing compounds, notably cisplatin. The first part of this review describes the differences between oxaliplatin and cisplatin in terms of their spectrum of activity and adduct formation and then goes on to discuss molecular and cellular experimental data that potentially explain them. Particular emphasis is placed on the differential role of DNA repair mechanisms. In addition, the anticancer effects of oxaliplatin are optimized when it is administered in combination with other anticancer agents, such as 5-fluorouracil, gemcitabine, cisplatin, or carboplatin; topoisomerase I inhibitors; and taxanes. In vitro and preclinical combination data that could optimize oxaliplatin-based chemotherapy are also reviewed. 相似文献
18.
Joshi KS Rathos MJ Mahajan P Wagh V Shenoy S Bhatia D Chile S Sivakumar M Maier A Fiebig HH Sharma S 《Molecular cancer therapeutics》2007,6(3):926-934
P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as a novel antineoplastic agent. In this study, we have selected a panel of human tumor cell lines and xenografts to allow determination of selectivity and efficacy of P276-00. When tested against a panel of 16 cisplatin-sensitive and cisplatin-resistant cell lines, the antiproliferative potential of P276-00 was found to be approximately 30-fold higher than cisplatin. Studies to show tumor sensitivity using clonogenic assay in 22 human xenografts indicated that P276-00 was approximately 26-fold more potent than cisplatin, and further, it was also found to be active against cisplatin-resistant tumors of central nervous system, melanoma, prostate, and renal cancers. Further, we studied the effects of P276-00 on cell cycle progression by flow cytometry using asynchronous and synchronous population of tumor and normal cells. Asynchronous population of human prostate carcinoma (PC-3) and human promyelocytic leukemia (HL-60) cells when exposed to P276-00 showed arrest of slow-growing PC-3 cells in G(2)-M with no significant apoptosis observed up to 72 h. Unlike PC-3, significant apoptosis was seen in fast-growing HL-60 cells at 6 h. However, synchronized human non-small cell lung carcinoma (H-460) and human normal lung fibroblast (WI-38) cells showed arrest of cells in G(1). H-460 cells undergo apoptosis, which increases with longer exposure to the compound and also after exposure to P276-00 for 48 h followed by recovery. In contrast, the normal cells (WI-38) remain arrested in G(1) with no significant apoptosis up to 72 h of exposure and also after 48 h of P276-00 treatment followed by recovery, confirming our previous results that P276-00 was less effective against normal cells compared with cancer cells. After promising in vitro results, P276-00 was checked for in vivo efficacy in murine tumor and human xenograft models. Growth inhibition of murine colon cancer (CA-51) was significant when P276-00 was administered i.p. at 50 mg/kg daily for 20 treatments. However, in murine lung carcinoma model (Lewis lung), an increased dose of 60 mg/kg (30 mg/kg twice daily) administered every alternate day i.p. for seven treatments showed significant inhibition in the growth. Further studies were undertaken to establish the efficacy profile of P276-00 in human tumor xenograft models. In the two xenograft models studied, P276-00 showed potent in vivo antitumor potential. Compound P276-00 at a dose of 35 mg/kg administered daily via the i.p. route for 10 days showed significant (P < 0.05) inhibition in the growth of human colon carcinoma HCT-116 xenograft. Furthermore, P276-00 at a dose of 50 mg/kg once daily and 30 mg/kg twice daily administered via i.p. route for 20 treatments significantly (P < 0.05) inhibited growth of human non-small cell lung carcinoma H-460 xenograft. Thus, the in vitro cellular potency, together with in vivo antitumor activity, confirms the potential of P276-00, a cyclin-dependent kinase inhibitor as an anticancer molecule. 相似文献
19.
Platinum-based anticancer agents: innovative design strategies and biological perspectives 总被引:11,自引:0,他引:11
The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum-based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA-Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2-diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA-Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt-based anticancer agents will materialize in the near future. 相似文献
20.
Cisplatin is nephrotoxic, but the mechanism by which cisplatin kills renal proximal tubule cells is not well defined. Inhibition of gamma-glutamyl transpeptidase or pyridoxal 5'-phosphate (PLP)-dependent enzymes blocks the nephrotoxicity. Our hypothesis is that cisplatin is metabolized to a renal toxin through a platinum-glutathione conjugate to a reactive sulfur-containing compound. The final step in this bioactivation is the conversion of a platinum-cysteine S-conjugate to a reactive thiol by a PLP-dependent cysteine S-conjugate beta-lyase. LLC-PK1 cells, a proximal tubule cell line with low cysteine S-conjugate beta-lyase activity, are used to study cisplatin nephrotoxicity. We proposed that the beta-elimination reaction catalyzed by cysteine S-conjugate beta-lyase is the rate-limiting step in the metabolism of cisplatin to a toxin in these cells. In this study, LLC-PK1 cells were transfected with human glutamine transaminase K, which catalyzes the beta-elimination reaction. Cisplatin was significantly more toxic in confluent monolayers of cells with increased cysteine S-conjugate beta-lyase activity. In contrast, carboplatin, a non-nephrotoxic derivative of cisplatin, was 20-fold less toxic than cisplatin in confluent cells, and its toxicity was not altered by overexpression of cysteine S-conjugate beta-lyase. We propose that carboplatin is not nephrotoxic because it is not metabolized through this pathway. Dividing cells were more sensitive to both cisplatin and carboplatin toxicity. Overexpression of cysteine S-conjugate beta-lyase activity had no effect on the toxicity of either drug. These data demonstrate that cisplatin kills quiescent renal cells by a mechanism that is distinct from the mechanism by which it kills dividing cells and that the renal toxicity of cisplatin is dependent on cysteine S-conjugate beta-lyase activity. 相似文献