Human Ovarian Cancer Cell A2780 Research Articles

Synthesis of novel supramolecular selenomolybdate as anticancer agents: An experimental and DFT computational analysis

A novel organic–inorganic material based on three-dimensional (3D) Strandberg-type polyoxoselenomolybdate, (C6H14N2)2[Se2Mo5O21]·2·6H2O (I, where C6H14N2 = DABCO cation) was successfully synthesized by solution process and characterized by scanning electron microscopy (SEM), infrared (FT-IR) and ultraviolet (UV–vis) spectroscopies, thermogravimetric analysis (TGA), cyclic voltammetry (CV) measurement. The electronic and electrochemical behavior of the compound was further evaluated as a function of pH and time via UV–vis spectroscopy and CV. Single crystal X-Ray diffraction (XRD) technique was used for complete structure elucidation. The title compound crystallizes in the non-centrosymmetric orthorhombic space group P212121, thus resulting in non-linear optical properties. The supramolecular framework exhibits a periodic arrangement of Strandberg clusters anions [Se2Mo5O21]4– connected to each other with water molecules and dabconium cations, through a network of hydrogen bonds and van der Waals interactions. The occurrence of intermolecular interactions, ensuring the cohesion between different entities, was assessed by density functional theory (DFT) calculations and Hirshfeld surface analysis. DFT calculations with different functionals have been used to better understand several properties like as RDG, QTAIMs, ELF, MEP and NLO.A good agreement was indeed found between the experimental and computational results. Furthermore, the (C6H14N2)2[Se2Mo5O21]·2·6H2O compound was tested for its biological activity. This selenomolybdate displayed a significant inhibitory effect on the growth of human ovarian cancer cells A2780, with an IC50 value of 4.05 ± 0.55 μM, being thus the first Strandberg-type polyoxometalate to show a significant anticancer activity.

Dipeptide-catalysed Michael reaction under physiological conditions: Examination of potential bioorthogonality

Reactions for drug synthesis under cell-like conditions or even inside living cells can potentially be used e.g., to minimize toxic side effects, to maximize bioactive compound efficacy and/or to address drug delivery problems. Those reactions should be bioorthogonal to enable the generation of drug-like compounds with sufficiently good yields. In the known bioorthogonal Michael reactions, using thiols and phosphines as nucleophiles (e.g., in CS and CP bond formation reactions) is very common. No bioorthogonal Michael addition with a carbon nucleophile is known yet. Therefore, the development of such a reaction might be interesting for future drug discovery research. In this work, the metal-free Michael addition between cyclohexanone and various trans-β-nitrostyrenes (CC bond formation reaction), catalysed by a dipeptide salt H-Pro-Phe-O-Na+, was investigated for the first time in the presence of glutathione (GSH) and in phosphate-buffered saline (PBS). We demonstrated that with electron-withdrawing substituents on the aromatic ring and in β-position of the trans-β-nitrostyrene yields up to 64% can be obtained under physiological conditions, indicating a potential bioorthogonality of the studied Michael reaction. In addition, the selected Michael products demonstrated activity against human ovarian cancer cells A2780. This study opens up a new vista for forming bioactive compounds via CC bond formation Michael reactions under physiological (cell-like) conditions.

Cytotoxic Properties of C17 Polyacetylenes from the Fresh Roots of Panax ginseng on Human Epithelial Ovarian Cancer Cells.

Although C17 polyacetylenes from Panax ginseng exhibit cytotoxic properties against various tumor cells, there have been few experiments on epithelial ovarian carcinoma cells. This study aimed to investigate the cytotoxic effects of C17 polyacetylenes from P. ginseng against ovarian cancer cell lines. Four unreported (1–4) and fifteen known (5–19) C17 polyacetylenes were obtained from the roots of P. ginseng using repeated chromatography (open column, MPLC, and preparative HPLC). The chemical structures of all the compounds were determined by analyzing their spectroscopic data (NMR, IR, and optical rotation) and HR-MS. The structures of new polyacetylenes were elucidated as (3S,8S,9R,10R)-(-)-heptadeca-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (1), (3S,8S,9R,10R)-(−)-heptadeca-1-en-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (2), (−)-haptadeca-9,10-epoxy-8-methoxy-4,6-diyne-3,11-diol (3), and (3R,9R,10R)-(+)-3-acetoxy-9,10-dihydroxyheptadeca-1-en-4,6-diyne (4), named ginsenoynes O, P, and Q, and 3-acetyl panaxytriol, respectively. Subsequently, in vitro experiments on A2780 and SKOV3 human epithelial ovarian carcinoma cells were performed to assess the cytotoxic properties of the isolates. Among the isolates, panaquinquecol 4 (15) exhibited the most remarkable cytotoxic effects on both human ovarian cancer cells A2780 (IC50 value of 7.60 μM) and SKOV3 (IC50 value of 27.53 μM). Therefore, C17 polyacetylenes derived from P. ginseng may warrant further investigation for their therapeutic potential in epithelial ovarian cancer.

Isoflavones Isolated from the Seeds of Millettia ferruginea Induced Apoptotic Cell Death in Human Ovarian Cancer Cells.

The seeds of Millettia ferruginea are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from M. ferruginea were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3’,4’-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.

Abstract 174: Preclinical activity of new liposomal formulation of doxorubicin (TLD-1)

Abstract Background: InnoMedica is a young company with focus on clinical translation of nanomedicine. The company employs its own manufacturing technology that gives rise to a novel liposome platform. The platform allows for specific shaping of nanosurfaces. This leads to a myriad of different particle designs with highly distinct biological functions. In a first approach, the lead-formulation TLD-1 (targeted liposomal doxorubicin) was developed in order to ameliorate chemotherapeutic outcome for patients, taking into account the patterns of biodistribution in the entire organism as well as nanoparticle-cell interactions and subcellular localisation. Methods: Pharmacologic properties of TLD-1 were investigated in vitro and in vivo. Human ovarian cancer cells A2780 were cultured in both 2D and 3D settings and antineoplastic activity of different formulations of doxorubicin was measured by quantification of cell viability. The same formulations were also compared in three animal models of cancer including murine breast cancer 4T1, human breast cancer MDA-MB231, and A2780. MDA-MB231 and A2780 cells were grown in vitro and injected subcutaneously (sc) in immunodeficient mice (Athymic Nude-Foxn1nu). 4T1 cells were injected either sc or in the mammary fat pad of immunocompetent mice (BALB/c). The different drug products were injected intravenously twice weekly for a total of three weeks. Activity was determined with caliper measurements of tumor diameters every three days. Animal body weight was recorded as index of toxicity. Doxorubicin was determined in plasma and tissues by HPLC-MS. Results: In 2D and 3D cell culture assays, TLD-1 showed a marked increase in cytotoxicity compared to Caelyx and was close to free drug. In all three animal models, TLD-1 showed activity superior to that of free doxorubicin given at the same dose and compared well to Caelyx both in terms of activity and toxicity. Conclusions: A couple of nanoparticulate features of TLD-1 liposomes are believed to attribute to the difference in antitumor activity. Cytotoxicity data from cell culture experiments indicate that TLD-1 liposomes are readily taken up by cancer cells and release their drug load into the cytoplasm. Commercial liposomes as in Caelyx seem to largely remain outside of cancer cells. In sum, TLD-1 is a novel and highly active antineoplastic nanodrug that has the potential to outperform free drug as well as commercial liposomal formulations of doxorubicin. Citation Format: Massimo Broggini, Federica Guffanti, Roberta Affatato, Lavinia Morosi, Patrick Buschor, Christoph Matthieu, Florian Weiss, Andreas Konig, Peter Halbherr, Stefan Halbherr. Preclinical activity of new liposomal formulation of doxorubicin (TLD-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 174. doi:10.1158/1538-7445.AM2017-174

A Specific Mixture of Nutrients Suppresses Ovarian Cancer A-2780 Tumor Incidence, Growth, and Metastasis to Lungs.

Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. Despite advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a specific nutrient mixture (EPQ) containing ascorbic acid, lysine, proline, green tea extract, and quercetin on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were all inoculated intraperitoneally (IP) with 2 × 106 cells in 0.1 mL of phosphate buffered saline (PBS) and randomly divided into two groups. Upon injection, the Control group (n = 6) was fed a regular diet and the EPQ group (n = 6) a regular diet supplemented with 0.5% EPQ. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed, and processed for histology. Lungs were inspected for metastasis. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with EPQ in triplicate at concentrations between 0 and 1000 μg/mL. Cell proliferation was measured via MTT assay, MMP-9 secretion via gelatinase zymography, invasion through Matrigel and morphology via hematoxylin and eosin (H & E) staining. All Control mice developed large ovarian tumors, whereas 5 out of 6 mice in the EPQ group developed no tumors, and one, a small tumor. Control mice also showed lung metastasis in 6 out of 6 mice, while no lung metastasis was evident in EPQ mice. Zymography demonstrated only MMP-9 expression, which EPQ inhibited in a dose-dependent fashion, with virtual total block at 250 μg/mL concentration. EPQ significantly inhibited invasion through Matrigel with total block at 250 μg/mL concentration. MTT showed dose-dependent inhibition of cell proliferation with EPQ, and H & E staining showed no morphological changes below 500 μg/mL EPQ. These results suggest that EPQ has therapeutic potential in the treatment of ovarian cancer by significantly suppressing ovarian tumor incidence and growth and lung metastasis, and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells.

Cisplatin and valproate released from the bifunctional [Pt(IV)Cl2(NH3)2(valproato)2] antitumor prodrug or from liposome formulations: who does what?

The cisplatin-sensitive human ovarian cancer cells A2780 have been challenged with cationic liposomes containing the single drug cisplatin or valproate or their combination with an approximate 1 : 2 molar ratio, i.e. the same ratio present in preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv), that releases such metabolites by intracellular Pt(iv) → Pt(ii) reduction. The results of this comparison confirm that valproate barely penetrates cells unless it is transported by liposomes or it is coordinated to a lipophilic Pt(iv) assembly. The two drugs have a synergistic action, cisplatin being the more potent antiproliferative agent. Even if the preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv) releases cisplatin and valproate in the same amount as the liposome formulation, the Pt(iv) derivative is more active. This important feature, common to all Pt(iv) complexes having very lipophilic carboxylates, is attributable to their propensity to remain in cells and to continuously bind DNA, unlike cisplatin that is partially removed from cells by efficient efflux pathways.

Abstract 4053: A unique nutrient mixture suppresses ovarian cancer growth of A-2780 by inhibiting invasion and MMP-9 secretion

Abstract Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. The American Cancer Society estimated that it would claim 14,250 lives in 2013. Despite the advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a unique nutrient mixture (NM) containing ascorbic acid, lysine, proline and green tea extract on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were inoculated by I.P. with 2×106 cells in 0.1ml PBS and randomly divided into two groups. Group A (n = 6) was fed a regular diet and group B (n = 6) a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed and processed for histology. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with NM in triplicate at concentrations between 0-1000 μg/ml. Cell proliferation was measured by MTT assay, MMP-9 secretion by gelatinase zymography, invasion through Matrigel and morphology by H&E staining. All control mice (Group A) developed large ovarian tumors, whereas 5 out of 6 mice in group B developed no tumors, and one, a small tumor. Zymography demonstrated only MMP-9 expression, which NM inhibited in a dose dependent fashion, with virtual total block at 250 μg/ml concentration. NM significantly inhibited invasion through Matrigel with total block at 250 μg/ml concentration. MTT showed dose dependent inhibition of cell proliferation with NM and H&E staining showed no morphological changes below 500 μg/ml NM. These results suggest that NM has therapeutic potential in treatment of ovarian cancer by significantly suppressing tumor growth and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells. Citation Format: M. Waheed Roomi, Matthias Rath, Aleksandra Niedzwiecki. A unique nutrient mixture suppresses ovarian cancer growth of A-2780 by inhibiting invasion and MMP-9 secretion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4053.

Evodiamine from Evodia rutaecarpa induces apoptosis via activation of JNK and PERK in human ovarian cancer cells

BackgroundEvodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2′3′-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism of EVO against the viability of human ovarian cancer cells is still unclear. PurposeA number of studies showed that chemotherapeutic benefits may result from targeting the endoplasmic reticular (ER) stress signaling pathway. The objective of the study is to investigate the mechanism by which ER stress protein PERK plays in EVO-induced apoptosis of human ovarian cancer cells. MethodsCell death analysis was performed by MTT assay, DNA fragmentation assay, and Giemsa staining. DiOC6 staining was used for mitochondrial membrane potential measurement. Protein levels were analyzed by Western blotting. Pharmacological studies using MAPK inhibitors and PERK inhibitor GSK2606414 were involved. ResultsThe viability of human ovarian cancer cells A2780, A2780CP, ES-2, and SKOV-3 was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells, DNA ladders, and cleavage of caspase 3 and poly(ADP ribose) polymerase (PARP) proteins. Decreased viability of cells was reversed by adding caspase inhibitors VAD and DEVD in SKOV-3 and A2780CP cells, and incubation of cells with JNK inhibitor SP600125 (SP) and JNKI, but not other MAPK and AKT inhibitors including PD98059, SB203580, significantly prevented the apoptosis elicited by EVO in human ovarian cancer cells. Furthermore, increased expression of phospho-eIF2α (peIF2α) and phospho-PERK (pPERK) proteins was detected in EVO-treated human ovarian cancer cells, and that was inhibited by adding JNK inhibitors SP600125 and JNKI. Application of a PERK inhibitor GSK2606414 showed a significant protection of human ovarian cancer cells A2780 and A2780CP from EVO-induced apoptosis. EVO disruption of mitochondrial membrane potential (MMP) was also inhibited by adding JNK or PERK inhibitors. The structure-activity relationship study indicated that the alkyl group at position 14 in EVO is important for apoptosis induction via activation of JNK and PERK in human ovarian cancer cells. ConclusionEvidence supporting EVO induction of apoptosis via activation of JNK and PERK to disrupt MMP in human ovarian cancer cells is provided, and the alkyl at position 14 is a critical substitution for the apoptotic actions of EVO.

Chemoenzymatic synthesis and cytotoxicity of oenanthotoxin and analogues

We developed a synthetic scheme for the synthesis of naturally occurring (14R)-oenanthotoxin and several analogs. Key-steps of this synthesis were an efficient homo-coupling of alkynes and a chemoenzymatic resolution of racemic oenanthotoxin using novozyme 435 and vinyl acetate. The compounds were screened for their cytotoxic activity using a photometric sulforhodamine B assays and several human tumor cell lines. Oenanthotoxin and many derivatives thereof were cytotoxic to tumor cell lines as well as to non-malignant mouse fibroblasts. The highest activity was determined for human ovarian cancer cells A2780 with EC50=3.8μM.

Increasing the selectivity of biologically active tetranuclear arene ruthenium assemblies

A series of arene ruthenium metalla-rectangles of general formula [(η6-p-cymene)4Ru4(μ4-embelin)2(μ2-N∩N)2](CF3SO3)4 was prepared from the embelin-derived metalla-clip (η6-p-cymene)2Ru2(μ4-embelin)Cl2 (1), silver triflate and several linear ditopic N-ligands (N∩N); pyrazine (prz), 4,4'-bipyridine (bpy), 1,2-bis(4-pyridyl)ethylene (bpe), 4,4'-azopyridine (azp) and di(pyridin-4-yl)oxalamide (bpo). The antiproliferative activity of these multinuclear arene ruthenium metalla-rectangles was evaluated in vitro on the human ovarian cancer cells A2780 and A2780cisR and on the noncancerous cell line HEK-293. Among these complexes, two rectangles, [(η6-p-cymene)4Ru4(μ4-embelin)2(μ2-bpy)2](CF3SO3)4 and [(η6-p-cymene)4Ru4(μ4-embelin)2(μ2-bpo)2](CF3SO3)4, display excellent activity and selectivity for cancer cells.

Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy

The photoeffect of new proflavine derivatives with DNA-binding and antitumour activities, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides (AcrDIMs), was studied to evaluate them as potential photosensitizers for photodynamic antitumor therapy. EPR measurements showed that superoxide radical anion and singlet oxygen were produced upon irradiation of AcrDIMs with UV-A light (>300nm) in the presence of molecular oxygen. This indicates that AcrDIMs may act as photosensitizers. The most active pentyl-AcrDIM and hexyl-AcrDIM displayed photocytotoxic effect toward the mouse lymphocytic leukemia cell line L1210 and human ovarian cancer cells A2780. Antitumor activity of pentyl-AcrDIM increased as high as about 12 times (72h incubation) after irradiation of A2780 cells (365nm, 1.05J/cm2). The photocytotoxicity seems to be associated with oxidative stress. Concerning the cell cycle, flow cytometry showed an arrest in the S-phase already 4h after irradiation. In a comet assay, no genotoxicity of AcrDIMs was found. Typical morphologic changes and formation of DNA-ladders indicated induction of apoptotic cell death, though no activation of caspase-3 was observed. Investigation of intracellular localization of pentyl-AcrDIM confirmed its partial accumulation in mitochondria and lysosomes. After irradiation of the A2780 cells, colocalization of pentyl-AcrDIM with monodansylcadaverine, a lysosomal dye, was proven, suggesting that lysosomes in the irradiated cells may be involved in the cell death.

Membrane damaging activity of a maslinic acid analog

Close inspection of human ovarian cancer cells A2780 in the course of an antitumor screening using maslinic acid analogs revealed for one of the compounds, 4-oxa-4-phenyl-butyl 2,3-dihydroxy-olean-12-en-28-oate (1), an unusual behavior. During the incubation of the cells with 1, at the perimeter of the cells or close by crystals were formed consisting of cholesterol and excess 1. Compound 1 was incorporated into the cell's membrane followed by an extrusion of cholesterol from the lipid rafts. As a consequence of the alterations of the cell membrane, a volume decrease was initiated that triggered apoptosis; this extends previous models on apoptosis initiating mechanisms.

Gold(iii) complexes inhibit growth of cisplatin-resistant ovarian cancer in association with upregulation of proapoptotic PMS2 gene

Various gold complexes have been known to overcome cisplatin resistance in cancer cells. Yet, their in vivo anti-tumor efficacies and detailed action mechanisms in overcoming this resistance remain largely unexplored. In this work we have established a xenograft model simultaneously consisting of both cisplatin-sensitive and cisplatin-resistant tumors by inoculating human ovarian cancer cells A2780 and its cisplatin-resistant variant A2780cis into different flanks of the same nude mouse. Towards this model, a gold(III) porphyrin complex [AuIII(TPP)]Cl (gold-1a, wherein [TPP]2− = meso-tetraphenylporphyrinato ligand) was found to effectively inhibit the growth of both kinds of tumors, while cisplatin failed to suppress the growth of A2780cis tumors under similar conditions. In both A2780 and A2780cis cells, gold-1a was found to transcriptionally upregulate postmeiotic segregation increased 2 (PMS2) which has DNA mismatch repair and proapoptotic functions. Suppression of PMS2 by RNA interference in A2780cis cells partially rescued the gold-1a-induced death of the cells, indicating that gold-1a inhibited growth of cisplatin-resistant ovarian cancer in association with upregulation of this gene. Two other stable gold(III) analogues including gold(III) octaethylporphyrin (2) and gold(III)-NHC (3) complexes also displayed similar anti-cancer activities on A2780cis cells and capability in PMS2 regulation. In contrast, a gold(I) phosphine complex (4), a gold(I) thiourea complex (5), KAuIIICl4 and cisplatin all displayed a preferential cytotoxicity only towards the cisplatin-sensitive A2780 cells. Taken together, this work has demonstrated the prospect of gold(III) complexes for the treatment of cisplatin-resistant/relapsed ovarian cancers.

"Atypical" multidrug resistance in human ovarian cancer cell line A2780 selected for resistance to doxorubicin (A2780 DX3).

Human ovarian cancer cells A2780, selected for resistance to doxorubicin (A2780-DX3), are cross-resistant to various other topoisomerase-II-targeted drugs but not to vinblastine. The parental cell line was very sensitive to doxorubicin-, mitoxantrone- or etoposide(VP16)-induced DNA single-strand breaks, under deproteinizing conditions. In contrast, little or no DNA strand breakage was seen in resistant A2780-DX3 cells, even at very high concentrations, indicating a good correlation, with cytotoxicity. No significant alterations in cellular drug uptake were observed in DX3 cells. Further studies showed that the nuclei isolated from resistant cells were also resistant to mitoxantrone- or VP16-induced single-strand breaks, indicating that nuclear modifications in resistant cells are responsible for this resistance. Catalytic activity in crude nuclear extracts from wild-type and DX3 cells was almost equal. However, an assay that specifically measures generation of 5'-protein-linked breaks in 32P-labeled 3 DNA revealed that, DNA cleavage activity in nuclear extract from the DX3 cell line is profoundly resistant to a stimulation by VP16. These data indicate that stimulation of topoisomerase-II-mediated DNA cleavage is responsible for topoisomerase-II-targeted drug-cytotoxicity rather than loss of normal topoisomerase catalytic function. These data support the hypothesis that A2780-DX3 cells display an "atypical" multidrug resistance.