Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment.

A lot of effort has been done to study how cancer cells react to low-oxygen tension, a condition known as hypoxia. Indeed, abnormal and dysfunctional blood vessels in the tumor are incapable to restore oxygenation, therefore perpetuating hypoxia, which, in turn, will fuel tumor progression, metastasis and resistance to antitumor therapies. Nevertheless, how stromal components including blood and lymphatic endothelial cells, pericytes and fibroblasts, as well as hematopoietic cells, respond to low-oxygen tension in comparison with their normoxic counterparts has been a matter of investigation in the last few years only and, to date, this field of research remains poorly understood. In general, opposing phenotypes can arise from the same stromal component when embedded in different tumor microenvironments, and, vice versa, different stromal components can have opposite reaction to the same tumor microenvironment. In this article, we will discuss the emerging link between tumor stroma and hypoxia, and how this complexity is translated at the molecular level.

Regulation of aspartate-derived amino acid homeostasis in potato plants (Solanum tuberosum L.) by expression of E. coli homoserine kinase.

The availability of the carbon backbone O-phosphohomoserine (OPHS) is critical to methionine (met) and threonine (thr) synthesis. OPHS derives from homoserine and is formed by homoserine kinase (HSK). To clarify the function of HSK in cellular metabolism, the E. coli HSK ortholog thrB was expressed in potato plants targeting the EcHSK protein to chloroplasts and to the cytosol. Both approaches resulted in up to 11 times increased total HSK enzyme activity. Transgenic plants exhibited reduced homoserine levels while met and thr did not accumulate significantly. However, the precursor cysteine and upstream intermediates of met such as cystathionine and homocysteine did indicating an accelerated carbon flow towards the end products. Coincidently, plants with elevated cytosolic levels of EcHSK exhibited a reduction in transcript levels of the endogenous HSK, as well as of threonine synthase (TS), cystathionine beta-lyase (CbL), and met synthase (MS). In all plants, cystathionine gamma-synthase (CgS) expression remained relatively unchanged from wild type levels, while S-adenosylmethionine synthetase (SAMS) expression increased. Feeding studies with externally supplied homoserine fostered the synthesis of met and thr but the regulation of synthesis of both amino acids retained the wild type regulation pattern. The results indicate that excess of plastidial localised HSK activity does not influence the de novo synthesis of met and thr. However, expression of HSK in the cytosol resulted in the down-regulation of gene expression of pathway genes probably mediated via OPHS. We integrated these data in a novel working model describing the regulatory mechanism of met and thr homeostasis.

Cell death-mediated antiviral effect of chitosan in tobacco.

The antiviral activity induced by chitosan (CHT), and the mechanisms underlying it, were studied in a tobacco-tobacco necrosis necrovirus (TNV) pathosystem. Treatments with 0.1% CHT enhanced tobacco inducible defenses against TNV, reducing significantly the virus-induced necrotic lesions (in a range from 32% to 83%). In planta, this resistance was associated with a network of callose deposits, micro-oxidative bursts and micro-hypersensitive responses (micro-HRs), as assessed, respectively, by aniline blue, 3,3'-diaminobenzidine (DAB) and Evans blue staining. In order to verify if CHT-elicited cell death could be regarded as an apoptotic process, tobacco bright yellow 2 (BY2) cell cultures were treated with different CHT concentrations, ranging from 0.01% to 0.1%. After 6 h about half of the cultured cells incubated in 0.05% CHT were Evans blue positive, showing some typical morphological features of apoptosis, such as cytoplasm shrinkage and nuclear chromatin condensation. The latter was checked by 4',6-diamino-2-phenylindole (DAPI) and ethidium bromide nuclear staining and was visible already at 2 h after treatment. Moreover, the cell death kinetic induced by CHT was delayed by Verapamil(R), a calcium channel blocker. Finally, electrophoresis of genomic DNA extracted from cultured cell after 48 h treatment showed internucleosomal fragmentation, visualized as a distinct ladder of DNA bands corresponding to oligonucleosomal units.

Maniobras para preservar continencia y potencia sexual en Prostatectomia Radical (PR) abierta y laparoscopica / Tecnical modifications to preserve continence and erectile function in open and laparoscopic radical prostactectomy (RP)

Introduccion: La incontinencia de orina y la disfuncion sexual, son las complicaciones mas frecuentes de la PR.Los abordajes anatomicos consiguieron una disminucion de su incidencia. Para mejorar estas complicaciones, se perfeccionaron algunos pasos de la tecnica basandonos en videos de PR abierta filmados con optica laparoscopica. Material y metodos: Se modifico el manejo del complejo venoso dorsal evitando involucrar fibras del esfinter en los puntos de hemostasia, el manejo de los puntos de la uretra evitando fijarla al tejido periuretral, la preservacion de los nervios erectores y la confeccion de la anastomosis vesico-uretral. Se comparo un grupo historico, analizado retrospectivamente, de 40 pacientes operados entre 10/1999 y 12/2001 con 40 pacientes operados entre 1/2002 y 12/2003, de analisis prospectivo, en quienes se implementaron las modificaciones tecnicas. Resultados: Se considero incontinencia de orina sin proteccion en 37/40 (92,5 por ciento) del grupo historico y 39/40 (97,5 por ciento) del grupo con modificaciones, continencia total en 29/40 (72,5 por ciento) y 32/40 (80 por ciento), erecciones espontaneas o con sildenafil en 22/35 (62,8 por ciento) y 27/37 (72,9 por ciento) y el tiempo para recuperacion de la ereccion 6,8 vs. 3,0 meses (P<0,05). Conclusiones: Las modificaciones introducidas disminuyeron la incidencia de la incontinencia y la disfuncion sexual, con diferencias significativas solo en el tiempo de recuperacion de la eleccion

Maniobras para preservar continencia y potencia sexual en Prostatectomia Radical (PR) abierta y laparoscopica / Tecnical modifications to preserve continence and erectile function in open and laparoscopic radical prostactectomy (RP)

Introduccion: La incontinencia de orina y la disfuncion sexual, son las complicaciones mas frecuentes de la PR.Los abordajes anatomicos consiguieron una disminucion de su incidencia. Para mejorar estas complicaciones, se perfeccionaron algunos pasos de la tecnica basandonos en videos de PR abierta filmados con optica laparoscopica. Material y metodos: Se modifico el manejo del complejo venoso dorsal evitando involucrar fibras del esfinter en los puntos de hemostasia, el manejo de los puntos de la uretra evitando fijarla al tejido periuretral, la preservacion de los nervios erectores y la confeccion de la anastomosis vesico-uretral. Se comparo un grupo historico, analizado retrospectivamente, de 40 pacientes operados entre 10/1999 y 12/2001 con 40 pacientes operados entre 1/2002 y 12/2003, de analisis prospectivo, en quienes se implementaron las modificaciones tecnicas. Resultados: Se considero incontinencia de orina sin proteccion en 37/40 (92,5 por ciento) del grupo historico y 39/40 (97,5 por ciento) del grupo con modificaciones, continencia total en 29/40 (72,5 por ciento) y 32/40 (80 por ciento), erecciones espontaneas o con sildenafil en 22/35 (62,8 por ciento) y 27/37 (72,9 por ciento) y el tiempo para recuperacion de la ereccion 6,8 vs. 3,0 meses (P<0,05). Conclusiones: Las modificaciones introducidas disminuyeron la incidencia de la incontinencia y la disfuncion sexual, con diferencias significativas solo en el tiempo de recuperacion de la eleccion(AU)

Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility.

Plexins encode receptors for semaphorins, molecular signals guiding cell migration, and axon pathfinding. The mechanisms mediating plexin function are poorly understood. Plexin activation in adhering cells rapidly leads to retraction of cellular processes and cell rounding "cell collapse"). Here we show that, unexpectedly, this response does not require the activity of Rho-dependent kinase (ROCK) nor the contraction of F-actin cables. Interestingly, integrin-based focal adhesive structures are disassembled within minutes upon plexin activation; this is followed by actin depolymerization and, eventually, by cellular collapse. We also show that plexin activation hinders cell attachment to adhesive substrates, blocks the extension of lamellipodia, and thereby inhibits cell migration. We conclude that plexin signaling uncouples cell substrate-adhesion from cytoskeletal dynamics required for cell migration and axon extension.

[Behavior of serum IgE and IgA in patients with allergic rhinitis treated with iodine bromide thermal water]. / Comportamento delle IGE e IGA sieriche in pazienti con rinite allergica trattata con acque salsobromoiodiche.

The aim of this study was to test the effects of the iodine bromide water of the thermal baths of Salsomaggiore on patients suffering from specific nonseasonal rhinitis (Dermatophagoides Farinae and Dermatophagoides Pteronyssinus). The patients, 80 in all, were divided in two groups (group A and group B). All of the patients underwent rhinoscopic examination, anterior rhinomanometry, prick test, rast screening, total IgE assay together with that of the other immunoglobulins (IgA, IgM, IgG), mucociliary clearance evaluation and were asked to evaluate their degree of nasal obstruction, before and after 30 days of treatment. Group A carried out the experiment by applying endonasal Acqua Sal spray seven times a day for 30 days; group B used oily drops for the same time and with the same frequency. At the end of the trial period, the patients in group A showed a 100% improvement in their subjective perception of their symptomatology, in comparison with a 33% improvement in the control group. A characteristic decrease in the IgE and increase in the IgA was observed in the serum of the patients who had been treated with Acqua Sal spray. Iodine bromide water has a general and local anti-inflammatory effect, which is also due to the activation of the corticosurrenal system (with a relative increase in cortisol). The cleansing action of hypertonic water in the nasal cavities must also be cited, as it minimizes contact between the mucosa and allergens.

Engineering of cysteine and methionine biosynthesis in potato.

Methionine and cysteine, two amino acids containing reduced sulfur, are not only an important substrate of protein biosynthesis but are also precursors of various other metabolites such as glutathione, phytochelatines, S-adenosylmethionine, ethylene, polyamines, biotin, and are involved as methyl group donor in numerous cellular processes. While methionine is an essential amino acid due to an inability of monogastric animals and human beings to synthesise this metabolite, animals are still able to convert methionine consumed with their diet into cysteine. Thus, a balanced diet containing both amino acids is necessary to provide a nutritionally favourable food or feed source. Because the concentrations of methionine and cysteine are often low in edible plant sources, e.g. potato, considerable efforts in plant breeding and research have been and are still performed to understand the physiological, biochemical, and molecular mechanisms that contribute to their synthesis, transport, and accumulation in plants. During the last decade molecular tools have enabled the isolation of most of the genes involved in cysteine and methionine biosynthesis, and the efficient plant transformation technology has allowed the creation of transgenic plants that are altered in the activity of individual genes. The physiological analysis of these transgenic plants has contributed considerably to our current understanding of how amino acids are synthesised. We focused our analysis on potato (Solanum tuberosum cv. Désirée) as this plant provides a clear separation of source and sink tissues and, for applied purposes, already constitutes a crop plant. From the data presented here and in previous work we conclude that threonine synthase and not cystathionine gamma-synthase as expected from studies of Arabidopsis constitutes the main regulatory control point of methionine synthesis in potato. This article aims to cover the current knowledge in the area of molecular genetics of sulfur-containing amino acid biosynthesis and will provide new data for methionine biosynthesis in solanaceous plants such as potato.

Antisense inhibition of threonine synthase leads to high methionine content in transgenic potato plants.

Methionine (Met) and threonine (Thr) are members of the aspartate family of amino acids. In plants, their biosynthetic pathways diverge at the level of O-phosphohomo-serine (Ser). The enzymes cystathionine gamma-synthase and Thr synthase (TS) compete for the common substrate O-phosphohomo-Ser with the notable feature that plant TS is activated through S-adenosyl-Met, a metabolite derived from Met. To investigate the regulation of this branch point, we engineered TS antisense potato (Solanum tuberosum cv Désirée) plants using the constitutive cauliflower mosaic virus 35S promoter. In leaf tissues, these transgenics exhibit a reduction of TS activity down to 6% of wild-type levels. Thr levels are reduced to 45% wild-type controls, whereas Met levels increase up to 239-fold depending on the transgenic line and environmental conditions. Increased levels of homo-Ser and homo-cysteine indicate increased carbon allocation into the aspartate pathway. In contrast to findings in Arabidopsis, increased Met content has no detectable effect on mRNA or protein levels or on the enzymatic activity of cystathionine gamma-synthase in potato. Tubers of TS antisense potato plants contain a Met level increased by a factor of 30 and no reduction in Thr. These plants offer a major biotechnological advance toward the development of crop plants with improved nutritional quality.

Preparation and functional characterization of thylakoids from Arabidopsis thaliana.

A protocol for the isolation of functional thylakoids from Arabidopsis thaliana leaves was developed. The critical factor in obtaining active, coupled and stable preparation is the inclusion of EDTA and EGTA in the grinding buffer. Preparations were characterized with respect to the whole or partial electron transport chain, ATP/NADPH, ATP/O(2) and PS II/chlorophyll ratios. Sensitivity to a light-chill photoinhibitory treatment was also determined by evaluating the decrease in both maximal photochemical efficiency (Fv/Fm) and in electron transport rate.

BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity.

Matrix metalloproteinases (MMPs) have been implicated in tumor cell invasion, metastasis, and angiogenesis. BAY 12-9566, a novel, non-peptidic biphenyl MMP inhibitor, has shown preclinical activity on a broad range of tumor models and is currently in clinical development. The purpose of this study was to investigate the antiangiogenic activity of BAY 12-9566. In vitro, BAY 12-9566 prevented matrix invasion by endothelial cells in a concentration-dependent manner (IC50 = 8.4x10(-7) M), without affecting cell proliferation. In vivo, oral daily administration of BAY 12-9566 (50-200 mg/kg) inhibited angiogenesis induced by basic fibroblast growth factor in the Matrigel plug assay, reducing the hemoglobin content of the pellets. Histological analysis showed a reduction in the amount of functional vessels within the Matrigel. We conclude that the MMP inhibitor BAY 12-9566 inhibits angiogenesis, a property that further supports its clinical development as an antimetastatic agent.

Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts.

On the basis of a structure-activity study of a new series of anthracycline disaccharides, we recently identified a doxorubicin analogue (MEN 10755) with a promising antitumor activity. In the present study, to better support the pharmacological interest of MEN 10755, we extended the preclinical evaluation of antitumor efficacy to a large panel of 16 human tumor xenografts, which originated from different clinicopathological types. Tumors with typical multidrug-resistant phenotype were excluded because MEN 10755 was found unable to overcome resistance mediated by transport systems. In the doxorubicin-responsive series, MEN 10755 exhibited a higher activity in three of five tumors, as documented by a more marked tumor growth inhibition and an increased value of log-cell kill. In the series of doxorubicin-resistant tumors, MEN 10755 was found effective in 6 of 11 tumors (1 breast, 3 lung, and 2 prostate carcinomas). The overall response rates were 31% and 69% for doxorubicin and MEN 10755, respectively. The improvement in drug efficacy was also supported by a substantial increase in the long-term survivor rate of animals implanted with responsive tumors. Most of the tumors refractory to doxorubicin and responsive to MEN 10755 were characterized by overexpression of the antiapoptotic protein Bcl-2. In one of these tumors (MX-1 breast carcinoma), we examined the ability of MEN 10755 to induce phosphorylation of Bcl-2 after a single treatment with therapeutic doses. The results indicated that, unlike doxorubicin, MEN 10755 induced protein phosphorylation. A similar modification was produced by Taxol, which is known to be very effective against the tumor. The correlation between drug efficacy and Bcl-2 phosphorylation may underly a peculiar feature related to improvement of efficacy of the disaccharide analogue. In conclusion, the present study supports some favorable features of the novel doxorubicin analogue in terms of both efficacy and tolerability with comparison to doxorubicin, although the improvement is somewhat tumor- and schedule-dependent.

Naamidine A is an antagonist of the epidermal growth factor receptor and an in vivo active antitumor agent.

The known 2-aminoimidazole alkaloid naamidine A (1) was isolated from a Fijian Leucetta sp. sponge as an inhibitor of the epidermal growth factor (EGF) receptor. The compound exhibited potent ability to inhibit the EGF signaling pathway and is more specific for the EGF-mediated mitogenic response than for the insulin-mediated mitogenic response. Evaluation in an A431 xenograft tumor model in athymic mice indicated that naamidine A exhibited at least 85% growth inhibition at the maximal tolerated dose of 25 mg/kg. Preliminary mechanism of action studies indicate that the alkaloid fails to inhibit the binding of EGF to the receptor and has no effect on the catalytic activity of purified c-src tyrosine kinase.

Eleutherobin, a novel cytotoxic agent that induces tubulin polymerization, is similar to paclitaxel (Taxol).

Eleutherobin is a novel natural product isolated from a marine soft coral that is extremely potent for inducing tubulin polymerization in vitro and is cytotoxic for cancer cells with an IC50 similar to that of paclitaxel. This compound is cross-resistant along with other multidrug-resistant agents against P-glycoprotein-expressing cells and is cross-resistant with paclitaxel against a cell line that has altered tubulin. In mechanistic studies, eleutherobin shares with paclitaxel the ability to induce tubulin polymerization in vitro and is most likely cytotoxic by virtue of this mechanism. Human colon carcinoma cells exposed to eleutherobin contain multiple micronuclei and microtubule bundles, and they arrest in mitosis, depending on concentration, cell line, and length of exposure. These morphological abnormalities appearing in cultured cells are indistinguishable from those induced by paclitaxel. Electron microscopy reveals that eleutherobin induces homogeneous populations of long, rigid microtubules similar to those formed by paclitaxel. Thus, eleutherobin is a new chemotype with a mechanism of action similar to that of paclitaxel and, as such, has promising potential as a new anticancer agent.

Doxorubicin disaccharide analogue: apoptosis-related improvement of efficacy in vivo.

BACKGROUND: Although doxorubicin remains one of the most effective agents for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical structures) that may have improved antitumor properties. We have synthesized a novel doxorubicin disaccharide analogue (MEN 10755) and have characterized some of its relevant biochemical, biologic, and pharmacologic properties. METHODS: The antitumor activity of this compound (MEN 10755) was studied in a panel of human tumor xenografts, including xenografts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells. MEN 10755 was compared with doxorubicin according to the optimal dose and schedule for each drug. The drug's cytotoxic effects, induction of DNA damage, and intracellular accumulation were studied in A2780 cells. DNA cleavage mediated by the enzyme topoisomerase II was investigated in vitro by incubating fragments of simian virus 40 DNA with the purified enzyme at various drug concentrations and analyzing the DNA cleavage-intensity patterns. Drug-induced apoptosis (programmed cell death) in tumors was determined with the use of MX-1 and POVD tumor-bearing athymic Swiss nude mice. RESULTS: MEN 10755 was more effective than doxorubicin as a topoisomerase II poison and stimulated DNA fragmentation at lower intracellular concentrations. In addition, MEN 10755 exhibited striking antitumor activity in the treatment of human tumor xenografts, including those of the doxorubicin-resistant breast carcinoma cell line MX-1. CONCLUSIONS: The high antitumor activity of MEN 10755 in human tumor xenografts, including doxorubicin-resistant xenografts, and its unique pharmacologic and biologic properties make this disaccharide analogue a promising candidate for clinical evaluation.

Preclinical antitumor activity of water-soluble paclitaxel derivatives.

PURPOSE: Five water-soluble paclitaxel derivatives were extensively evaluated for their antitumor activities relative to the parent drug. METHODS: Both subcutaneous (s.c.) murine (M109 lung) and human (A2780 ovarian, L2987 lung) tumor models were used for this purpose. RESULTS: Consecutive daily intravenous (i.v.) paclitaxel therapy of mice bearing s.c. M109, beginning on day 4 or 5 posttumor implant and continuing for 5 days, resulted in a range of maximum gross log cell kill (LCK) values (reflective of delays in tumor growth) and maximum relative median survival time (% T/C) values (reflective of increases in lifespan) of 1.0-2.1 and 132-162% (and one outlying result of 235%), respectively. Against the same tumor model, using the same treatment schedule, each of the water-soluble derivatives was active, with maximum LCK of 1.3-2.5 and T/C of 124-254%. These LCK and %T/C values were always within 0.5 LCK and 15%, respectively, of the concomitantly obtained maximum effects of paclitaxel. When tested in several experiments against staged (50-100 mg) s.c. A2780 tumors, using various i.v. treatment schedules, the water-soluble derivatives achieved a maximum LCK of 1.4-3.8. Evaluated in parallel, paclitaxel achieved a maximum LCK of 2.1-4.5 following every other day x 5 i.v. therapy. When paclitaxel was assayed in several experiments using the staged (50-100 mg) s.c. L2987 tumor model, maximum LCK of 0.9->4.1 were produced following every other day x 5 i.v. therapy. Concomitant testing of the water-soluble derivatives, using the same i.v. treatment schedule, resulted in maximum LCK of 0.2->4.1. In each of the tumor models used, the consistently active, and usually the most active, water-soluble derivative was BMS-185660. The levels of activity observed were comparable (within 1 LCK) to those achieved concomitantly using paclitaxel, and its potency was only slightly inferior to the parent drug. CONCLUSIONS: Based on the evaluations performed in three distal site tumor models, we conclude that BMS-185660 is a water-soluble paclitaxel derivative with preclinical antitumor activity comparable to that of the parent drug.

Effect of linker variation on the stability, potency, and efficacy of carcinoma-reactive BR64-doxorubicin immunoconjugates.

The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.

Paclitaxel (Taxol(R)) inhibits motility of paclitaxel-resistant human ovarian carcinoma cells.

The effect of paclitaxel on the adhesive and motility properties of human ovarian carcinoma cell lines was investigated. Paclitaxel significantly inhibited the motility of OVCAR 5, SK-OV-3, and HOC-1OTC ovarian carcinoma cell lines (IC50 = 2.1 x 10(-8), 2 x 10(-9), and 1.9 x 10(-8) m, respectively) but did not affect the adhesion of these cells to the subendothelial matrix. The association between inhibition of motility and cytotoxic activity was investigated using an A2780 subclone (1A9) and three paclitaxel-resistant variants (designated 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18). Although paclitaxel did not significantly affect the adhesion to subendothelial matrix of the sublines, it completely inhibited their migration. Inhibition of migration was similar in 1A9 cells and the resistant sublines, with an IC50 of 1 x 10(-8) for 1A9 cells and 5.4 x 10(-9), 1.1 x 10(-8), and 5.2 x 10(-9) m for 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively. Paclitaxel inhibited motility induced by soluble attractant (chemotaxis) and immobilized attractant (haptotaxis). Inhibition of cell motility occurred in the absence of an antiproliferative effect, because higher concentrations of paclitaxel were required to inhibit tumor cell proliferation (IC50 = 1.9 x 10(-7) and 4.6 x 10(-6), 1 x 10(-5), and 3.1 x 10(-6) m for 1A9 and 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively). These data show that paclitaxel is a potent inhibitor of ovarian carcinoma cell motility and that this activity is independent of its cytotoxic activity.