Functional Single-Chain Polymer Nanoparticles: Targeting and Imaging Pancreatic Tumors in Vivo.

The development of tools for the early diagnosis of pancreatic adenocarcinoma is an urgent need in order to increase treatment success rate and reduce patient mortality. Here, we present a modular nanosystem platform integrating soft nanoparticles with a targeting peptide and an active imaging agent for diagnostics. Biocompatible single-chain polymer nanoparticles (SCPNs) based on poly(methacrylic acid) were prepared and functionalized with the somatostatin analogue PTR86 as the targeting moiety, since somatostatin receptors are overexpressed in pancreatic cancer. The gamma emitter 67Ga was incorporated by chelation and allowed in vivo investigation of the pharmacokinetic properties of the nanoparticles using single photon emission computerized tomography (SPECT). The resulting engineered nanosystem was tested in a xenograph mouse model of human pancreatic adenocarcinoma. Imaging results demonstrate that accumulation of targeted SCPNs in the tumor is higher than that observed for nontargeted nanoparticles due to improved retention in this tissue.

Q-Switched Nd:YAG Laser Removal of Facial Amateur Tattoos in Patients With Fitzpatrick Type VI: Case Series.

INTRODUCTION: Q-switched neodymium:YAG (Nd:YAG) lasers are reported to be gold standard for laser tattoo removal. In particular, the Q-switched Nd:YAG laser at 1064 nm is widely recognized for the removal of blue/black amateur tattoos. However, treatment modalities in Fitzpatrick Type VI skin carry a greater risk of complications including alterations in pigmentation compared to fairer skin (Fitzpatrick Type I-IV skin). Therefore, the aim of this case series was to describe with the use of the Q-Switched Nd:YAG laser, the removal of carbon-based amateur tattoos on patients with Fitzpatrick Type VI skin as an effective and safe method. METHODS: Twenty- five patients with Fitzpatrick type VI skin, from Ethiopian origins, with facial tribal tattoos, were treated with the Q- Switched Nd:YAG laser at 1064 nm. Digital images were taken upon every treatment and the clearance rates of the tattoo was evalu- ated by imaging software. RESULTS: We observed an average tattoo clearance rate of 95% among the 45 facial tattoos in 25 patients presented in the case series with minimal pigmentary and textual changes evident. DISCUSSION: These positive aesthetic results have a signi cant psychosocial impact on the lives of those with Fitzpatrick Type VI skin, in particular the Ethiopian Jewish population. J Drugs Dermatol. 2016;15(11):1448-1452..

Adipocytes Viability After Suction-Assisted Lipoplasty: Does the Technique Matter?

BACKGROUND: Suction-assisted lipoplasty (SAL; liposuction) is an established aesthetic procedure in plastic surgery. The main parameters differentiating one method of lipoplasty from another are safety, consistency of results, and other more technical parameters. Due to the recent popularity of lipotransfer, the quality of extracted fat has become a relevant parameter. We compare the viability of extracted adipocytes after dry SAL, hyper-tumescent PAL (power-assisted lipoplasty), and water-assisted lipoplasty (WAL). METHODS: We used fluorescent microscopy to differentiate viable from necrotic/apoptotic cells after liposuction using each of the mentioned methods. RESULTS: The ratio of living cells between the three methods was significantly different with dry liposuction yielding inferior ratios (p = 0.011). When omitting extreme results, we found that the body-jet technique (WAL) yielded higher ratios of living cells than the hyper-tumescent technique (p < 0.001). The total number of cells was highest in the hyper-tumescent method (p = 0.013). CONCLUSIONS: Our results indicate that the hyper-tumescent technique yields the highest number of cells, whereas the body-jet technique yields the highest living cells ratio. The dry technique is clearly inferior to both. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Radiotherapy-induced basal cell carcinomas of the scalp: are they genetically different?

BACKGROUND: The treatment of tinea capitis using radiotherapy was introduced at the beginning of the twentieth century. In Israel, between 1949 and 1960, approximately 17,000 children underwent radiotherapy treatments for tinea capitis (actual numbers are probably higher due to irradiation in countries of origin as a prerequisite for immigration). Skin cancer presents a major problem for patients who underwent irradiation for the treatment of tinea capitis [aggressive biological behavior, multiple basal cell carcinomas (BCCs), up to 40 lesions in a single patient, with no predisposing condition such as Gorlin's or Bazex's syndromes]. There are ample data in the literature concerning the molecular changes in ultraviolet (UV) radiation-induced BCCs. However, similar data regarding ionizing radiation-induced BCCs are scarce. One work found higher rates of p53 and PTCH (both are tumor suppressor genes whose alterations are associated with BCC formation and frequency, but not biological behavior) abnormalities in post ionizing radiation BCCs. The absence of documented differences in gene expression that would account for a different biological behavior of radiotherapy-related BCCs, coupled with the aggressive and recurrent nature of these lesions, has propelled us to examine these differences by comparing gene expression in BCCs of the scalps of patients who were previously irradiated for tinea capitis in their childhood and of the scalps of patients who were not. METHODS: Tissue samples of excised scalp BCCs from seven previously irradiated patients (five male, two female) and seven not previously irradiated patients (six male, one female) were frozen upon excision and genetically analyzed using DNA microarray chips. RESULTS: No correlation was found between previous ionizing irradiation and gene expression. CONCLUSIONS: The negative results of this study, coupled with the observation of aggressive biological behavior of BCCs in previously irradiated patients merit further attention. Other explanations for the aggressive biological behavior of radiotherapy-induced BCCs come to mind. One such explanation could be that the difference between the groups lies not in the tumor itself, but in the host, who is more susceptible to the local destruction caused by the tumor due to changes in the surrounding tissue (e.g., impaired blood supply due to radiation, structural damage in seemingly healthy skin). This hypothesis will be the focus of further research. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Systemic dysregulation of CEACAM1 in melanoma patients.

It was previously shown that CEACAM1 on melanoma cells strongly predicts poor outcome. Here, we show a statistically significant increase of serum CEACAM1 in 64 active melanoma patients, as compared to 48 patients with no evidence of disease and 37 healthy donors. Among active patients, higher serum CEACAM1 correlated with LDH values and with decreased survival. Multivariate analysis with neutralization of LDH showed that increased serum CEACAM1 carries a hazard ratio of 2.40. In vitro, soluble CEACAM1 was derived from CEACAM1(+), but neither from CEACAM1(-) melanoma cells nor from CEACAM1(+) lymphocytes, and directly correlated with the number of CEACAM1(+) melanoma cells. Production of soluble CEACAM1 depended on intact de novo protein synthesis and secretion machineries, but not on metalloproteinase function. An unusually high percentage of CEACAM1(+) circulating NK and T lymphocytes was demonstrated in melanoma patients. CEACAM1 inhibited killing activity in functional assays. CEACAM1 expression could not be induced on lymphocytes by serum from patients with high CEACAM1 expression. Further, expression of other NK receptors was impaired, which collectively indicate on a general abnormality. In conclusion, the systemic dysregulation of CEACAM1 in melanoma patients further denotes the role of CEACAM1 in melanoma and may provide a basis for new tumor monitoring and prognostic platforms.

A novel fractional micro-plasma radio-frequency technology for the treatment of facial scars and rhytids: a pilot study.

INTRODUCTION: Fractional ablative and non-ablative lasers have gained popularity in the treatment of acne scars and rhytids due to their efficacy and improved tolerability. Plasma and radio frequency (RF) have also emerged as methods for ablative or non-ablative energy delivery. We report preliminary experience with a novel fractional micro-plasma RF device for the treatment of facial acne scars and rhytids. METHODS: Sixteen patients with facial acne scars or rhytids were treated at 4-week intervals. Treatment parameters were titrated to an immediate end point of moderate erythema. The clinical end point for cessation of treatment was the attainment of satisfactory clinical results. Results were monitored photographically up to 3 months after treatment. RESULTS: Acne scars showed marked improvement after two to four treatments. Facial rhytids demonstrated reduced depth after two treatments and marked improvement after four treatments. Treatment was well tolerated by all participants, with transient erythema and short downtime. These results provide initial evidence for the safety and effectiveness of fractional micro-plasma RF as a low-downtime and well-tolerated modality for the treatment of acne scars and facial rhytids.

Silicone nipple shields: an innovative postoperative dressing technique after nipple reconstruction.

BACKGROUND: The newly reconstructed nipple is extremely sensitive to mechanical pressure and shearing forces, which can cause flap necrosis and sloughing of the skin, eventually promoting infection. Current available dressing solutions are cumbersome, inefficient, displeasing, or otherwise not readily obtainable. METHODS: In this study, 10 patients with newly reconstructed nipples were instructed to use breastfeeding nipple shields as the sole means of nipple dressing after the reconstruction procedure. RESULTS: No complications were observed overall. Patients reported full adherence to the postoperative dressing regimen as well as ease of use, availability, low costs, and pleasing aesthetic appearance under garments. DISCUSSION: Silicone breastfeeding nipple shields offer an efficient, affable, cheap, widely available, and aesthetically pleasing form of postoperative dressing for reconstructed nipples. Their use may enhance patient compliance with the dressing regimen and lower the postoperative complication rate.

Dynamic expression of protective CEACAM1 on melanoma cells during specific immune attack.

An efficient immune response against tumours depends on a well-orchestrated function of integrated components, but is finally exerted by effector tumour-infiltrating lymphocytes (TIL). We have previously reported that homophilic CEACAM1 interactions inhibit the specific killing and interferon-gamma (IFN-gamma) release activities of natural killer cells and TIL. In this study a model for the investigation of melanoma cells surviving long coincubation with antigen-specific TIL is reported. It is demonstrated that the surviving melanoma cells increase their surface CEACAM1 expression, which in turn confers enhanced resistance against fresh TIL. Furthermore, it is shown that this is an active process, driven by specific immune recognition and is at least partially mediated by lymphocyte-derived IFN-gamma. Similar results were observed with antigen-restricted TIL, either autologous or allogeneic, as well as with natural killer cells. The enhanced CEACAM1 expression depends, however, on the presence of IFN-gamma and sharply drops within 48 hr. This may be a mechanism that allows tumour cells to transiently develop a more resistant phenotype upon recognition by specific lymphocytes. Therefore, this work substantiates the melanoma-promoting role of CEACAM1 and marks it as an attractive target for novel immunotherapeutic interventions.

The safest method of sternal wire extraction post-midsternotomy closure.

BACKGROUND: An incident of fatal pericardial bleeding immediately after the extraction of a sternal wire prompted a search for the most appropriate method for removing sternotomy wire sutures. A model sternum was devised to explore this problem, and several commonly used techniques for wire extraction were evaluated. METHODS: A wooden sternal model was constructed to simulate the dimensional properties of a sternum overlying the mediastinal cavity, and to imitate its tensile characteristics. A Monofil CrNi-316L (Johnson & Johnson, Brunswick, NJ, USA), No. 7 CCS, 9 metric, 4x45-cm wire was passed vertically through drilled holes. The suture was then crossed and pulled, thus joining the two boards and approximating the wire to their deep surface. A latex balloon filled with dye was placed inside under the boards. Wire holders were used to extract the wires, using a linear pulling technique and a coiling around the wire-holder tip technique. Sixty repetitions were performed for each method. RESULTS: In 60 trials of direct linear wire pulling, balloon rupture occurred in 33 (55%), whereas tearing was noted only 15 times out of 60 attempts (25%) when the tense coiling method was used. CONCLUSIONS: Sternotomy wire sutures should be extracted using a controlled technique that ensures safety to vital tissues in close proximity to the sternal bone. The tense coiling procedure offers superior safety when compared to the direct pulling process, demonstrated by a lower incidence of balloon rupture because of the lesser degree of wire flexure. This technique has become the method of choice in our medical center.

Diagnostic targeting of colon cancer using a novel fluorescent somatostatin conjugate in a mouse xenograft model.

Colorectal carcinoma is one of the more prevalent, highly malignant human tumors, occurring in about 7% of the population. However, if diagnosed and treated in its early stages, colon cancer is curable. In our study, we used a mouse xenograft model to investigate the capability of a fluorescent conjugate of a novel synthetic somatostatin (SST) analog to improve detection of human colorectal tumors that are characterized by over-expressed SST receptors. Human HT-29 colon carcinomas were induced in nude mice. After administration of the fluorescent SST conjugate, in vivo low- and high-magnification fluorescence microscopy, as well as high-resolution spectrally resolved imaging were performed, and the time-dependent biodistribution was determined quantitatively (using fiber-optic spectroscopy). Administration of the conjugate (at concentrations of 6 mg/kg body weight) enabled targeting small (1-5 mm diameter) tumors with high sensitivity and selectivity. Toxicity studies at dosages up to 1,000 mg/kg body weight did not reveal any drug related abnormalities. In conclusion, the SST conjugate significantly enhanced the detection of HT-29 colon tumors by fluorescence imaging because of a 5- to 8-fold increase in the contrast between malignant and normal tissues.

Quantification of water compartmentation in cell suspensions by diffusion-weighted and T(2)-weighted MRI.

When studying water diffusion in biological systems, any specific signal attenuation curve may be reproduced by a broad range of mathematical functions. Our goals were to quantify the diffusion and T(2) relaxation properties of water in a simple biological system and to study the changes that occur in osmotically stressed cells. Human breast cancer cells were incubated in isotonic or hypotonic osmotic buffers. Diffusion-weighted and T(2)-weighted magnetic resonance images were acquired during sedimentation over 12 h. Diffusion-weighted imaging (DWI) data were analyzed with a biexponential fit, the Kärger model for exchange between two freely diffusing populations and the Price-modified Kärger model accounting for restricted diffusion in spherical geometry. We found that only the Price model provided an accurate quantitative description for water diffusion in both cell systems, independent of acquisition parameters, over the entire density range. Model-derived cell radii, intracellular volume fractions and transmembrane water exchange times were in good agreement with results calculated from light microscopy and with model-free exchange times. T(2) data indicated two populations in fast exchange, with volume fractions clearly different from DWI populations. Hypotonic stress led to higher slow apparent diffusion coefficient, longer T(2) and lower membrane permeability. The tortuosity in a hypotonic cell suspension complied with the Wang model for spherical geometry. Quantitative characterization of biological systems is obtainable by DWI, using appropriate modeling, accounting for water restriction and exchange between compartments.

Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart.

BACKGROUND: Activated macrophages have a significant role in wound healing and damaged tissue repair. We sought to explore the ability of ex vivo activated macrophages to promote healing and repair of the infarcted myocardium. METHODS AND RESULTS: Human activated macrophage suspension (AMS) was prepared from a whole blood unit obtained from young donors in a closed sterile system and was activated by a novel method of hypo-osmotic shock. The AMS (approximately 4 x 10(5) cells) included up to 43% CD14-positive cells and was injected into the ischemic myocardium of rats (n=8) immediately after coronary artery ligation. The control group (n=9) was treated with saline injection. The human cells existed in the infarcted heart 4 to 7 days after injection, as indicated by histology, human growth hormone-specific polymerase chain reaction, and magnetic resonance imaging (MRI) tracking of iron oxide-nanoparticle-labeled cells. After 5 weeks, scar vessel density (+/-SE) (25+/-4 versus 10+/-1 per mm2; P<0.05), myofibroblast accumulation, and recruitment of resident monocytes and macrophages were greater in AMS-treated hearts compared with controls. Serial echocardiography studies, before and 5 weeks after injection, showed that AMS improved scar thickening (0.15+/-0.01 versus 0.11+/-0.01 cm; P<0.05), reduced left ventricular (LV) diastolic dilatation (0.87+/-0.02 versus 0.99+/-0.04 cm; P<0.05), and improved LV fractional shortening (31+/-2 versus 20+/-4%; P<0.05), compared with controls. CONCLUSIONS: Early after myocardial infarction, injection of AMS accelerates vascularization, tissue repair, and improves cardiac remodeling and function. Our work suggests a novel clinically relevant option to promote the repair of ischemic tissue.

"Competitive quenching": a mechanism by which perihydroxylated perylenequinone photosensitizers can prevent adverse phototoxic damage caused by verteporfin during photodynamic therapy.

Incorporation of photodynamic therapy into clinical practice for induction of vascular photo-occlusion highlights the need to prevent adverse phototoxicity to sensitive juxtaposed tissues, particularly in the retina. We developed a system termed "competitive quenching" to prevent adverse phototoxic damage. It involves differential compartmentalization of a photoactivator to the intravascular compartment for photoexcitation and delivery of phototoxicity to targeted vessels. A different photodynamic agent is partitioned to the extravascular retinal space to quench reactive oxygen species generated by photosensitization, thereby protecting the adjacent retinal tissues from adverse phototoxicity. The absorption spectra of quenchers must span wavelengths that are shorter and excluded from the spectral range of photoexcitation light to prevent photoactivation of the quencher. Perihydroxylated perylenequinones were found to be suitable to function as "competitive quenchers" with the prototype hypericin identified as a potent quencher. Here we examined the mechanisms operative in competitive quenching and suggest that hypericin forms a complex with verteporfin, thereby quenching singlet oxygen formation. Furthermore, we show that hypericin, with six phenolic hydroxyls, protects retinal and endothelial hybridoma cells from phototoxicity more effectively than the dimethyl tetrahydroxy helianthrone structural analog with only four such phenolic hydroxyls. The findings suggest that hydroxyl numbers contribute to the efficacy of competitive quenching.

Pigmented lesions clinic for early detection of melanoma: preliminary results.

BACKGROUND: Early detection of malignant melanoma of the skin is the most important factor in patient survival. Naked-eye diagnostic sensitivity and specificity are low. Patients with multiple nevi are at high risk to develop melanomas and the clinical follow-up of such patients is difficult, resulting in missed melanomas on the one hand and unnecessary biopsies on the other. OBJECTIVES: To describe the set-up of a special clinic aimed at early detection of melanoma and follow-up of high risk patients and preliminary results from 20 months of operation. METHODS: We established a pigmented lesions clinic based on a digital photography studio enabling documentation and comparison over time of full body photography and dermoscopy. RESULTS: In the first 20 months of work, 895 patients were seen, 206 of them for follow-up visits. A total of 29,254 photos were taken. Altogether, 236 lesions were suspicious (either clinically or dermoscopically) and the patients were advised to excise them. Seven melanomas were found in this initial examination (which did not include long-term follow-up). CONCLUSIONS: With multimode photographic cutaneous surveillance, early detection of melanoma in high risk patients has been reported. Our clinic utilizes the same techniques and diagnostic algorithm as other leading clinics throughout the world, thus enabling us to deliver better follow-up for those patients.

Burns in Israel: demographic, etiologic and clinical trends, 1997-2003.

BACKGROUND: Burns are a major public health problem, with long hospitalization stay in both intensive care units and general wards. In Israel about 5% of all hospitalized injuries are burn injuries. There are no long-term epidemiological studies on burn injuries in adults in Israel. OBJECTIVES: To identify risk factors for burn injuries and provide a starting point for the establishment of an effective prevention plan. METHODS: We analyzed the demographic, etiologic and clinical data of 5000 burn patients admitted to the five major hospitals with burn units in Israel during a 7 year period (1997-2003). Data were obtained from the records of the Israeli National Trauma Registry. The differences between various groups were evaluated using the chi-square test. RESULTS: Male gender was twice as frequent as female gender in burn patients (68.0% vs. 31.9%), and non-Jewish ethnicity was more common when considering their proportion in the total population (62.3% vs. 36.8%). Second and third-degree burns with body surface areas less than 10% constituted the largest group (around 50%). The largest age group was 0-1 years, constituting 22.2% of the cases. Inhalation injury was uncommon (1.9%). The most common etiologies were hot liquids (45.8%) and open fire (27.5%). Children less than 10 years old were burnt mainly by hot liquids while the main cause of burns for adults > 20 years old was an open flame. The majority of burns occurred at home (58%); around 15% were work related. The mean duration of hospitalization was 13.7 days (SD 17.7); 15.5% were in an intensive care unit with a mean duration of 12.1 days (SD 17.1). Surgical procedures became more common during the period of the study (from 13.4% in 1998 to 26.59% in 2002, average 19.8%). The mortality rate was 4.4%. We found a strong correlation between burn degree and total body surface area and mortality (0.25% mortality for 2nd to 3rd-degree burns with less than 10% TBSA, 5.4% for 2nd to 3rd-degree burns with 20-39% TBSA, and 96.6% for burns > 90% TBSA). The worst prognosis was for those over the age of 70 (mortality rate 35.3%) and the best prognosis was for the 0-1 year group (survival rate 99.6%). CONCLUSIONS: The groups at highest risk were children 0-1 years old, males and non-Jews (the incidence rate among non-Jews was 1.5 times higher than their share in the general population). Those with the highest mortality rate were victims of burns > 90% TBSA and patients older than 70. Most burns occurred at home.

Late-onset facial abscess formation after cosmetic soft tissue augmentation with bio-alcamid.

Bio-Alcamid (BA) (polyalkylimide) was introduced in Europe in 2001. It is a nonresorbable injectable filler for soft tissue augmentation, indicated for a wide variety of clinical applications in reconstructive and cosmetic surgery in conditions where subcutaneous volumetric compensation is required. Although BA biocompatibility was approved by a European Union Certificate (CE), the substance is not a natural component of biologic tissues, and thus inflammation and infection are still potential risks. The authors present a case of BA infection after minor trauma 3 years after bilateral injections to the malar regions in a 43-year-old woman, causing an abscess that required surgical drainage and parenteral antibiotics.

Convection-enhanced drug delivery: increased efficacy and magnetic resonance image monitoring.

Convection-enhanced drug delivery (CED) is a novel approach to directly deliver drugs into brain tissue and brain tumors. It is based on delivering a continuous infusion of drugs via intracranial catheters, enabling convective distribution of high drug concentrations over large volumes of the target tissue while avoiding systemic toxicity. Efficient formation of convection depends on various physical and physiologic variables. Previous convection-based clinical trials showed significant diversity in the extent of convection among patients and drugs. Monitoring convection has proven to be an essential, yet difficult task. The current study describes the application of magnetic resonance imaging for immediate assessment of convection efficiency and early assessment of cytotoxic tissue response in a rat brain model. Immediate assessment of infusate distribution was obtained by mixing Gd-diethylenetriaminepentaacetic acid in the infusate prior to infusion. Early assessment of cytotoxic tissue response was obtained by subsequent diffusion-weighted magnetic resonance imaging. In addition, the latter imaging methodologies were used to establish the correlation between CED extent and infusate's viscosity. It was found that low-viscosity infusates tend to backflow along the catheter track, whereas high-viscosity infusates tend to form efficient convection. These results suggest that CED formation and extent may be significantly improved by increasing the infusate's viscosities, thus increasing treatment effects.

In vivo magnetic resonance imaging of pancreatic tumors using iron oxide nanoworms targeted with PTR86 peptide.

To cut the high mortality rate of malignant disease such as pancreatic cancer, development of newly diagnostic probes for early stage detection of tumor lesions is required. Multimodal imaging nanoprobes allowing targeted and real time functional/anatomical imaging of tumors meet the demands. For this purpose, a MRI/optical dual-modality probe based on biodegradable magnetic iron oxide nanoworms has been developed. The cross-linked surface of nanoworms were anchored to fluorescent dyes and to FITC.PTR86; a novel synthetic peptide with high affinity towards somatostatin receptors. Combination of various in vitro techniques including Prussian blue staining, fluorescent microscopy and fluorescence activated cell sorting (FACS) have been performed to explore the interaction of developed nanoprobe with pancreatic tumor cell lines. Together with in vivo studies in a xenograft mouse model of human pancreatic adenocarcinoma and ex vivo investigations, the results show the efficient imaging and targeting of pancreatic tumors by our newly developed nanosystem using both MRI and optical imaging modalities.

Galactorrhea complicating wound healing following reduction mammaplasty.

Galactorrhea complicating wound healing following reduction mammaplasty occurs rarely; only isolated cases have been reported in recent years. We report the case of a 25-year-old woman who presented with delayed healing and dehiscence of surgical wounds 3 weeks following vertical scar reduction mammaplasty. During surgical debridement, spontaneous discharge of milk in the wound was noted. Serum prolactin levels were high, and she was treated with carbegoline, a dopamine agonist, which suppressed the prolactin secretion and led to rapid cessation of lactation. A second debridement and delayed primary closure were performed to achieve a satisfactory postoperative result.

Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop.

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.