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Pardaxin, a pore-forming antimicrobial peptide that encodes 33 amino acids was isolated from the Red Sea Moses sole, Pardachirus mamoratus. In this study, we investigated its antitumor activity in human fibrosarcoma (HT-1080) cells and epithelial carcinoma (HeLa) cells. In vitro results showed that the synthetic pardaxin peptide had antitumor activity in these two types of cancer cells and that 15μg/ml pardaxin did not lyse human red blood cells. Moreover, this synthetic pardaxin inhibited the proliferation of HT1080 cells in a dose-dependent manner and induced programmed cell death in HeLa cells. DNA fragmentation and increases in the subG1 phase and caspase 8 activities suggest that pardaxin caused HeLa cell death by inducing apoptosis, but had a different mechanism in HT1080 cells., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Lovastatin (Lov), bisphosphonates (BP) and metformin (Met) are widely used drugs, having in common that they interfere with the mevalonate pathway (MP). The MP generates isoprene moieties required for the function of regulatory GTPases controlling cell proliferation and survival. Here, we addressed the question whether MP inhibitors interfere with the anti-tumor efficacy of anticancer drugs. We comparatively analyzed the effect of equitoxic doses of Lov, BP and Met on cell viability, cell cycle progression, apoptosis and DNA damage response (DDR) of human osteo- and fibrosarcoma cells exposed to doxorubicin or cisplatin. We found that Lov, BP and Met modulated the anticancer drug sensitivity of sarcoma cells in an agent-, dose and time-dependent fashion. Mostly, the MP inhibitors increased the cytotoxicity of the anticancer drugs in an additive manner. MP modulators differed from each other regarding their impact on anticancer drug-induced DNA damage response as measured by the phosphorylation status of SAPK/JNK, Chk-1 and H2AX as well as p53 protein level. In this regard, lovastatin and metformin turned out as the most effective inhibitory drugs. The data show that MP inhibitors can affect the anti-tumor efficacy of anticancer drugs and impact the DDR of human sarcoma cells., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

A generation 5 PEGylated (PEG 1100) polylysine dendrimer, conjugated via a stable amide linker to OtBu protected methotrexate (MTX), was previously shown to have a circulatory half-life of 2 days and to target solid tumors in both rats and mice. Here, we show that deprotection of MTX and substitution of the stable linker with a matrix metalloproteinase (MMP) 2 and 9 cleavable linker (PVGLIG) dramatically increased plasma clearance and promoted deposition in the liver and spleen (50-80% of the dose recovered in the liver 3 days post dose). Similar rapid clearance was also seen using a scrambled peptide suggesting that clearance was not dependent on the cleavable nature of the linker. Surprisingly, dendrimers where OtBu capped MTX was linked to the dendrimer surface via the hexapeptide linker showed equivalent in vitro cytotoxicity against HT1080 cells when compared to the uncapped dendrimer and also retained the long circulating characteristics of the stable constructs. The OtBu capped MTX conjugated dendrimer was subsequently shown to significantly reduce tumor growth in HT1080 tumor bearing mice compared to control. In contrast the equivalent dendrimer comprising uncapped MTX conjugated to the dendrimer via the same hexapeptide linker did not reduce tumor growth, presumably reflecting very rapid clearance of the construct. The results are consistent with the suggestion that protection of the α-carboxyl group of methotrexate may be used to improve the circulatory half-life and reduce the liver accumulation of similar MTX-conjugated dendrimers, while still retaining antitumor activity in vivo.

Scope: Capsaicin is a cancer-suppressing agent. The aim of our study was to determine the effect of capsaicin on tumor invasion and migration; the possible mechanisms involved in this inhibition were investigated in human fibrosarcoma cells., Methods and Results: We employed invasion, migration and gelatin zymography assays to characterize the effect of capsaicin on HT-1080 cells. Transient transfection assays and immunoblot analysis were performed to study its molecular mechanisms of action. Capsaicin inhibited the epidermal growth factor (EGF)-induced activation of matrix metalloproteinase (MMP)-9 and MMP-2, and further inhibited cell invasion and migration. Capsaicin decreased the EGF-induced expression of MMP-9, MMP-2, and MT1-MMP, but did not alter TIMP-1 and TIMP-2 levels. Capsaicin suppressed EGF-induced c-Jun and c-Fos nuclear translocation, and also abrogated the EGF-induced phosphorylation of EGF receptor (EGFR), focal adhesion kinase (FAK), protein kinase C (PKC), phosphatidylinositol 3-Kinase (PI3K)/Akt, extracellular regulated kinase (ERK)1/2, and JNK1/2, an upstream modulator of AP-1. Furthermore, the EGFR inhibitor inhibited EGF-induced MMP-9 expression, as well as AP-1 activity and cell migration., Conclusion: Capsaicin inhibited the EGF-induced invasion and migration of human fibrosarcoma cells via EGFR-dependent FAK/Akt, PKC/Raf/ERK, p38 mitogen-activated protein kinase (MAPK), and AP-1 signaling, leading to the down-regulation of MMP-9 expression. These results indicate the role of capsaicin as a potent anti-metastatic agent, which can markedly inhibit the metastatic and invasive capacity of fibrosarcoma cells., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Soft tissue sarcoma (STS) is a rare malignancy that is generally resistant to chemotherapy. We investigated the ability of the histone deacetylase inhibitor vorinostat to sensitize STS cells versus normal fibroblasts to chemotherapy. Fibrosarcoma, leiomyosarcoma, and liposarcoma cells and normal fibroblasts were treated with vorinostat to determine effects on proliferation and basal apoptosis as measured by total cell number and cleaved caspase 3 staining. Effects on histone deacetylases (HDAC) activity were confirmed by Western blotting for acetylated histone H3. A clinically relevant dose of vorinostat that had no effect on basal apoptosis was selected to examine altered sensitivity to doxorubicin. The effects of vorinostat, doxorubicin, or the combination on fibrosarcoma growth in vivo were determined in a xenograft model. Tumor volume was measured biweekly and HDAC activity and cell death were assessed by immunohistochemical analysis of acetylated histone H3, cleaved caspase 3, and TUNEL staining. Vorinostat inhibited proliferation and induced histone acetylation without affecting basal apoptosis levels. Combined treatment with vorinostat and doxorubicin synergistically induced apoptosis in vitro in fibrosarcoma but not leiomyosarcoma, liposarcoma, or normal fibroblasts. In nude mice, the combination of vorinostat and doxorubicin inhibited fibrosarcoma xenograft growth further than either agent alone. Cell death, as measured by cleaved caspase 3 and TUNEL staining, was greatest in xenografts from mice treated with vorinostat and doxorubicin. Vorinostat inhibits growth and induces chemosensitivity in fibrosarcoma cells in vitro and in vivo, suggesting that the combination of vorinostat and chemotherapy may represent a novel treatment option for this STS subtype. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:623-632, 2011., (Copyright © 2010 Orthopaedic Research Society.)

Tumor-draining lymph node (TDLN) ablation is routinely performed in the management of cancer; nevertheless, its usefulness is at present a matter of debate. TDLN are central sites where T cell priming to tumor antigens and onset of the antitumor immune response occur. However, tumor-induced immunosuppression has been demonstrated at TDLN, leading to downregulation of antitumor reaction and tolerance induction. Tolerance in turn is a main impairment for immunotherapy trials. We used a murine immunogenic fibrosarcoma that evolves to a tolerogenic state, to study the cellular and molecular mechanisms underlying tolerance induction at the level of TDLN and to design an appropriate immunotherapy. We determined that following a transient activation, the established tumor induces signs of immunosuppression at TDLN that coexist with local and systemic evidences of antitumor response. Therefore, we evaluated the feasibility of removing TDLN in order to eliminate a focus of immunosuppression and favor tumor rejection; but instead, a marked exacerbation of tumor growth was induced. Combining TDLN ablation with the in vivo depletion of regulatory cells by low-dose cyclophosphamide and the restoring of the TDLN-derived cells into the donor mouse by adoptive transference, resulted in lowered tumor growth, enhanced survival and a considerable degree of tumor regression. Our results demonstrate that important antitumor elements can be eliminated by lymphadenectomy and proved that the concurrent administration of low-dose chemotherapy along with the reinoculation of autologous cytotoxic cells provides protection. We suggest that this protocol may be useful, especially in the cases where lymphadenectomy is mandatory.

Aims and Background: Infantile fibrosarcomas are soft tissue sarcomas that are diagnosed at or soon after birth. In the present study, we retrospectively evaluated clinical characteristics, treatment modalities and outcome of patients diagnosed with infantile fibrosarcoma at our institution., Methods: A retrospective review was conducted to evaluate demographic characteristics, presenting features, type and timing of surgery, other treatment modalities and survival characteristics., Results: Nine males and 2 females were diagnosed with infantile fibrosarcoma between 1970-2008. The initial surgical procedure was subtotal resection in 4 patients, gross-total resection in 3 and biopsy in 4. Neoadjuvant chemotherapy was given to 10 patients. Three patients died, one for the disease and 2 from complications of therapy. Eight patients are under follow-up with no evidence of disease for 1.3 to 13.5 years. None of the patients in the series underwent amputation., Conclusions: Owing to the chemosensitive nature of the tumor and possibility of spontaneous regression, neoadjuvant chemotherapy should be considered to prevent extensive or mutilating surgery.

Background: Cytokines play a key role in the immune response to developing tumors, and therefore modulating their levels and actions provides innovative strategies for enhancing the activity of antigen presenting cells and polarizing towards T helper 1 type response within tumor microenvironment. One of these approaches could be the employment of plant extracts that have cytokine immunomodulation capabilities. Previously, we have shown that the Eriobotrya japonica hydrophilic extract (EJHE) induces proinflammatory cytokines in vitro and in vivo., Methods: The present study explored the in vivo immunomodulatory effect on interferon-gamma (IFN-γ), interleukin-17 (IL-17), and transforming growth factor-beta 1 (TGF-β1) evoked by two water-extracts prepared from EJ leaves in the tissues of normal and Meth-A-fibrosarcoma bearing mice., Results: Intraperitoneal (i.p.) administration of 10 μg of EJHE and EJHE-water residue (WR), prepared from butanol extraction, increased significantly IFN-γ production in the spleen (p < 0.01) and lung (p < 0.03) tissues at 6-48 hours and suppressed significantly TGF-β1 production levels (p < 0.001) in the spleen for as long as 48 hours. The latter responses, however, were not seen in Meth-A fibrosarcoma-bearing mice. On the contrary, triple i.p. injections, 24 hours apart; of 10 μg EJHE increased significantly IFN-γ production in the spleen (p < 0.02) while only EJHE-WR increased significantly IFN-γ, TGF-β1 and IL-17 (p < 0.03 - 0.005) production within the tumor microenvironment of Meth-A fibrosarcoma. In addition, the present work revealed a significant prolongation of survival time (median survival time 72 days vs. 27 days of control, p < 0.007) of mice inoculated i.p. with Meth-A cells followed by three times/week for eight weeks of i.p. administration of EJHE-WR. The latter prolonged survival effect was not seen with EJHE., Conclusions: The therapeutic value of EJHE-WR as an anticancer agent merits further investigation of understanding the effect of immunomodulators' constituents on the cellular components of the tissue microenvironment. This can lead to the development of improved strategies for cancer treatment and thus opening up a new frontier for future studies.

To improve the pharmacological profile of tumor necrosis factor alpha (TNF-α), we have synthesized a new PEGylated prodrug, PEG-vcTNF-α, using a cathepsin B-sensitive dipeptide (valine-citrulline, vc) to link branched PEG and TNF-α. PEG-modified TNF-α without the dipeptide linker (PEG-TNF-α) and unconjugated TNF-α were also tested as controls. It was found for the first time that TNF-α released from PEG-vcTNF-α was specifically dependent on the presence of cathepsin B. PEG-vcTNF-α induced higher cytotoxicity and greater apoptosis against L929 murine fibrosarcoma cells than PEG-TNF-α. Reversal of these effects by a cathepsin-B inhibitor confirmed that these effects were mediated by cathepsin B-specific release of TNF-α. In vivo pharmacokinetics studies demonstrated that the plasma stability of PEG-vcTNF-α was significantly increased compared to TNF-α. Finally, the improved anticancer efficacy of PEG-vcTNF-α and the distinct activities among the three formulations confirmed the positive contribution of both PEGylation and the dipeptide linkage to the improved drug-like properties of PEG-vcTNF-α. The results here indicate that linking proteins and PEG via the cathepsin B-sensitive dipeptide may be a promising strategy for developing protein therapeutics.

The objective of this study is to investigate the effect of molecular size and terminal structure of poly(ethylene glycol) (PEG) on the antitumor activity of PEG-modified fullerene (C60). PEG samples with different terminal structures and molecular weights were covalently coupled to C60 and their superoxide anion generation, in vitro or in vivo antitumor activity, and body distribution were assessed for the effect of the photosensitizer, used in photodynamic therapy (PDT), on the tumor. Irrespective of the molecular weight and terminal structure of PEG used, the C60-PEG conjugates exhibited a similar ability of superoxide anion generation and in vitro antitumor activity. On the contrary, a strong suppression of the in vivo tumor growth was observed for the C60-PEG conjugates prepared with methyl-terminated PEG with the highest molecular weight, which showed the longest half-life period in the blood circulation and the highest tumor accumulation among all the conjugates used. It is concluded that the superior tumor targetability of C60-PEG conjugates is one of the keys to enhance the PDT activity.

Pardaxin is an antimicrobial peptide (AMP) that was first isolated from secretions of the Red Sea Moses sole. The role of pardaxin in inducing apoptosis for preventing cancer has not yet been investigated. In the present study, we examined the antitumor activity of pardaxin against human fibrosarcoma HT-1080 cells; pardaxin inhibited cell proliferation by inducing apoptosis, as demonstrated by an increase in the externalization of plasma membrane phosphatidylserine and the presence of chromatin condensation. Additionally, pardaxin-treated cells showed elevation of caspase-3/7 activities, disruption of the mitochondrial membrane potential, and accumulation of reactive oxygen species (ROS) production. Inhibition of ROS production and caspase-3/7 activities reduced pardaxin-induced effects. Taken together, these findings suggest that pardaxin may be a potential anticancer agent for selectively inducing apoptosis in cancer cells.

Our previous results demonstrated that silibinin induced autophagic and apoptotic cell death dependent on reactive oxygen species (ROS especially H(2)O(2) and [image omitted] ) in HT1080 cells. In this study, we further show that p38-NF-κB pathway is involved in silibinin-induced ROS-mediated autophagy. Cells were pretreated with serum-free media for 24 h before being treated with silibinin. Generation of ROS and autophagy was detected in 15 min and 1 h, respectively. Development of autophagy was supported by an upregulated expression of Beclin-1 and conversion of light chain (LC3-I-LC3-II). Expression of p38/p-p38 and transposition of NF-κB from cytoplasm to nuclei were also increased. Inhibitors of p38 and NF-κB and scavengers of H(2)O(2) and O(2)(*-) reduced both generation of ROS and simultaneous occurrence of silibinin-induced autophagy. Besides, expression of p38/p-p38 and transposition of NF-κB from cytoplasm to nuclei were decreased by these two ROS scavengers. ROS and p38-NF-κB pathway were possibly cooperated in a positive feedback mechanism. Inhibition of p38, NF-κB, H(2)O(2), or O(2)(*-) rescued cells from silibinin-induced death in a long-term (12 h) manner. According to the previous study that silibinin-induced autophagy was a positive regulator of apoptotic cell death, it was possible that ROS and p38-NF-κB mediated silibinin-induced autophagy and eventually led to cell death.

Animal tumor bioassays and in vitro cell culture systems have demonstrated that epigallocatechin-3-O-gallate (EGCG), the predominant catechin in green tea, possesses anti-proliferative and pro-apoptotic effects on various cancer cells and tumors. In this study, we investigated the effects of EGCG on cell growth, cell cycle progression, and apoptosis in human fibrosarcoma HT-1080 cells. The involvement of p53, Bcl-2, Bax, caspases, and nuclear factor-κB (NF-κB) was examined as a mechanism for the anti-cancer activity of EGCG. Time-dependent intracellular trafficking of EGCG was also determined using fluorescein isothiocyanate (FITC)-conjugated EGCG (FITC-EGCG). Our data show that EGCG treatment caused dose-dependent cell growth inhibition, cell cycle arrest at the G(0)/G(1) phase, and DNA fragmentation suggesting the induction of apoptosis in HT-1080 cells. Immunoblot analysis revealed that the expression of p53, caspase-7 and -9 as well as the ratio of Bax/Bcl-2 protein increased significantly with higher EGCG concentrations and longer incubation times. Moreover, expression of phosphorylated NF-κB/p65 in HT-1080 cells was inhibited by EGCG treatment in a dose-dependent manner, while that of unphosphorylated NF-κB/p65 remained unaffected. Here we also reveal time-dependent internalization of FITC-EGCG into the cytosol of HT-1080 cells and its subsequent nuclear translocation. These results suggest that EGCG may interrupt exogenous signals directed towards genes involved in proliferation and cell cycle progression. Taken together, our data indicate that HT-1080 apoptosis may be mediated through the induction of p53 and caspases by the pro-oxidant activity of internalized EGCG, as well as suppression of Bcl-2 and phosphorylated NF-κB by the antioxidant activity of EGCG.

Our previous research demonstrated that hepatic-protectant silibinin induced autophagy in human fibro-sarcoma HT1080 cells through reactive oxygen species (ROS) pathway. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced autophagy and reversed silibinin's growth-inhibitory effect; besides, PFT-α decreased the activation of caspase-3, a crucial executor of apoptosis. Silibinin upregulated expression of p53/phosphorylated-p53 (p-p53) in a time-dependent manner. Catalase (scavenger of H(2)O(2)), superoxide dismutase (SOD) (scavenger of O(2)(•-)), and SB203580 (inhibitor of p38) attenuated upregulation of p53 expression, suggesting that p53 might be partially regulated by ROS-p38 pathway. On the other hand, c-Jun N-terminal kinase (JNK) increased autophagic death in silibinin-treated cells, and JNK/p-JNK expression was upregulated by silibinin time-dependently. Inhibition of JNK by SP600125 did not influence generation of ROS. Scavengers of H(2)O(2) or O(2)(•-) showed no effect on expression of JNK/p-JNK, indicating that JNK might not correlate with ROS in this process. However, activation of p53 was suppressed by SP600125; therefore the function of p53 was possibly controlled by JNK as well. Western blotting analysis showed that PFT-α reduced activation of extracellular regulated kinase1/2 (ERK1/2) and expression of protein kinase B (PKB, or Akt)/p-Akt. PD98059 (inhibitor of mitogen-activated protein kinase kinase (MEK)/ERK) and wortmannin (inhibitor of phosphoinositide 3-kinase (PI3K)/Akt) enhanced silibinin's cytotoxicity. Wortmannin augmented silibinin-induced autophagy, while PD98059 did not affect autophagic ratio. These results suggest that silibinin might induce p53-mediated autophagic cell death by activating ROS-p38 and JNK pathways, as well as inhibiting MEK/ERK and PI3K/Akt pathways.

The use of central venous catheters (CVCs) represents an important step in the management of the surgical, onco-hematology and critically ill patients. CVCs in neonates, like in adult patients, are mainly used to infuse hyperosmolar solutions, to take blood samples and for hemodynamic monitoring. The need for CVCs is higher in neonates than in adults. Poor peripheral access and the high demand for IV access and blood samples are already valuable indications for a CVC.

The methanolic extract and its EtOAc-soluble fraction from the rhizomes of Zingiber cassumunar inhibited invasion of human fibrosarcoma HT 1080 cells. From the EtOAc-soluble fraction, eight new phenylbutanoids, cassumunols A-H, were isolated together with 30 known constituents. The structures of new phenylbutanoids were elucidated on the basis of chemical and physicochemical evidence. Principal constituents were examined the inhibitory effects on the invasion of HT 1080 cells. Among them, phlain I and III, (E)-1-(3,4-dimethoxyphenyl)buta-1,3-diene, (E)-1-(2,4,5-trimethoxyphenyl)buta-1,3-diene, and (-)-β-sesquiphellandrene showed anti-invasion effects. Interestingly, (E)-1-(2,4,5-trimethoxyphenyl)buta-1,3-diene [inhibition (%) 46.8 ± 7.2 (p<0.05) at 30 µM] significantly inhibited the invasion, and only a weak cytotoxic effect was observed.

Unlabelled: Chaetocin, an antibiotic produced by Chaetomium species fungi, was recently found to have antimyeloma activity. Here we examined whether chaetocin has anticancer activities against solid tumors. Chaetocin inhibited the growth of mouse and human hepatoma grafts in nude mice. Immunohistochemical analyses revealed that chaetocin inhibits hypoxia-inducible factor-1α (HIF-1α) expression and vessel formation in the tumors. Chaetocin also showed antiangiogenic anticancer activities in HIF-1α(+/+) fibrosarcoma grafted in mice, but not in HIF-1α(-/-) fibrosarcoma. Biochemical analyses showed that chaetocin down-regulated HIF-1α and the transcripts of HIF-1 target genes including vascular endothelial growth factor in hepatoma tissues and in various hepatoma cell lines. Based on the reported literature, unsuccessful efforts were made to determine the mechanism underlying the action of chaetocin. Unexpectedly, chaetocin was found to cause the accumulation of HIF-1α premessenger RNA (pre-mRNA) but to reduce mature mRNA levels in hepatoma cells and tissues. Such an effect of chaetocin was not observed in cell lines derived from normal cells, and was cell type-dependent even among cancer cell lines., Conclusions: Our results suggest that chaetocin could be developed as an anticancer agent to target HIF-1 in some cancers including hepatoma. It is also suggested that the HIF-1α pre-mRNA splicing is a novel therapeutic target for controlling HIF-1-mediated pathological processes., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Objective: Given the fact that Mullerian Inhibiting Substance (MIS) causes complex remodeling of the urogenital ridge and regression of the Mullerian ducts during male embryonic development, we examined whether MIS could affect similar cell properties such as migration and invasion that could contribute ultimately to micro-metastasis of cancers arising from Mullerian tissues. MIS receptor expressing cell lines found to be invasive and migratory in vivo are examined in an in vivo assay that is cost-effective., Methods: We designed in vitro and in vivo experiments to determine if MIS inhibited the movement of cancer lines IGROV-1, HEp3, MDA-MB-231, and HT1080 in cell culture invasion/migration chamber assays and in chick embryo metastasis assays., Results: MIS, at concentrations below those that inhibit cell proliferation, blocked in vitro invasion and in vivo migration of epithelial cancer cells that express the MIS receptor., Conclusions: While our laboratory has previously established MIS as an inhibitor of cancer cell proliferation using in vitro assays and in vivo xenografts, we now show that MIS can also inhibit in vivo tumor migration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Fullerene [C60] included in polyethylene glycol (PEG) at a composing ratio of 1:350 w/w was examined for anticancer effects upon photodynamic therapy (PDT). Human connective tissue-derived fibrosarcoma cells HT1080 were decreased for a viability of 50% or 30%, by 3-h administration with PEG-fullerene [C60] at 50 or 100 ppm fullerene [C60] equivalent, respectively, subsequent rinsing out and irradiation with visible light (400-600 nm, 140 J/cm2: 450-fold as intense as in average outdoor), whereas the same tissue type-derived normal fibroblastic cells DUMS16 retained a viability of 93% or 85% under the same conditions. Anticancer effects were dependent on PEG-fullerene [C60] concentrations and irradiation doses, and scarcely exerted by PEG-fullerene [C60] alone, irradiation alone, or by fullerene [C60]-free PEG combined with irradiation, suggesting that the active principle may be fullerene [C60] as small as 0.0028 wt% versus the whole compound. Irradiation with PEG-fullerene [C60] occurred in intracellular DNA fragmentation according to TUNEL assay, and produced reactive oxygen species (ROS) such as hydroperoxides and peroxyl radicals or superoxide anion radicals in HT1080 cells as demonstrated by CDCFH-DA assay or nitroblue tetrazolium assay, respectively. Thus, PEG-fullerene [C60] is expected to be applied to anticancer PDT with scarce side effects on normal cells.

Galanthus nivalis agglutinin (GNA)-related lectin family, a superfamily of strictly mannose-binding specific lectins, has been well-known to possess several biological functions including apoptosis-inducing activities. However, the precise mechanisms of GNA-related lectins to induce apoptosis remains to be clarified. In this study, we showed that Polygonatum cyrtonema lectin (PCL) and Ophiopogon japonicus lectin (OJL), the two mannose-binding GNA-related lectins, could induce murine fibrosarcoma L929 cell apoptosis. In addition, we found that there was a close link between their sugar-binding and apoptosis-inducing activities. Interestingly, we further confirmed that the mechanism of lectin-induced apoptosis was a caspase-dependent pathway. Moreover, we found that the two lectins could amplify tumor necrosis factor α (TNFα)-induced apoptosis. Taken together, these findings would open a new perspective for GNA-related lectins as potential anti-tumor agents., (Crown Copyright © 2010. Published by Elsevier GmbH. All rights reserved.)

Background: Src, a non-receptor tyrosine kinase frequently overexpressed and highly activated in malignancies, has been associated with a poor patient prognosis. The aim of the present studies was to examine the impact of an Src inhibitor (saracatinib) on a highly metastatic murine sarcoma cell line (KHT)., Materials and Methods: Phosphorylation of Src and downstream effectors was determined using Western immunoblotting. Cell cycle was analyzed by flow cytometry using propidium iodide DNA staining, migration and invasion in modified Boyden chambers, activated MMP-9 by gel zymography, and visualization of pSrc and pFAK by confocal immunofluorescence. The number of KHT lung nodules in saracatinib-treated mice was compared to controls., Results: Saracatinib inhibited major pathways in the metastatic cascade in vitro, including Src and FAK activation. Functions required for metastasis, such as migration and invasion, were reduced when cells were exposed to 0.5 μM and 1.0 μM saracatinib, respectively (p<0.0001). Pretreatment of KHT cells with either 1 μM or 5 μM saracatinib prior to tail vein injection decreased lung colonies in mice from 13.0 to 5.0 (p<0.05) and less than 1.0 (p<0.01), respectively., Conclusion: These findings suggest that Src inhibition by saracatinib may reduce the metastatic activity of tumor cells.

Background: The immunomodulatory properties of polyuridylic acid (PolyU) make it a promising agent in cancer immunotherapy. However, there is limited information on its direct effects on tumor cells., Materials and Methods: TLR8 mRNA and protein expression in soft tissue sarcoma (STS) and bone sarcoma (BS) cell lines were determined by PCR and flow cytometry, respectively. Apoptosis and proliferation assays were performed using annexin V staining and BrdU incorporation assays, respectively. A relative cell enumeration was evaluated with WST-1 reagent. Expression levels of apoptotic proteins were evaluated by Western blotting., Results: We demonstrate that PolyU treatment resulted in a significant decrease in STS and BS cell count by inducing apoptosis and inhibition of cell proliferation. All cell lines examined expressed TLR8 and the effect of PolyU was partially mediated through TLR8. Several apoptotic proteins including caspases were activated or increased in STS cells after treatment with PolyU. Administration PolyU resulted in significant growth inhibition of STS without any observable adverse effects in mouse xenograft tumor models., Conclusions: These results elucidate the effect of PolyU in STS and BS cells and demonstrate that PolyU may be a potential therapeutic agent for STS and BS., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The extracellular tumor microenvironment is acidified, whereas the intracellular pH of tumor and stromal cells is neutral. cis-Urocanic acid (cis-UCA), an endogenous compound of the skin, can acidify the cytosol by transporting protons into the cells. This phenomenon, termed the protodynamic concept, was studied here in human cancer cells. cis-UCA dose-dependently reduced the number of viable human melanoma, cervical carcinoma, and fibrosarcoma cells at weakly acidic extracellular pH. The intracellular pH decreased by up to 0.5 pH units in a concentration-dependent manner with 0.3-30  m cis-UCA at extracellular pH 6.5 but not at pH 7.4. Under the same conditions, 30  mM cis-UCA induced annexin-V binding and activation of caspase-3 in A2058 melanoma cells as signs of apoptotic cell death. Finally, growth of human melanoma xenografts in SCID mice was suppressed by 60% following intratumoral injection of cis-UCA. Accordingly, the percentage of tumor necrosis and active caspase-3-immunopositive cells increased, whereas proliferation activity decreased. These results identify cis-UCA as an anticancer agent inhibiting melanoma growth by immediate intracellular acidification followed by apoptotic cell death in vivo.

To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).

Trabectedin is a novel antineoplastic agent approved as monotherapy in patients with advanced soft tissue sarcoma (STS) after failure of standard therapy with anthracyclines or ifosfamide, or patients who are unsuited to receive these agents. Some histotypes of STSs appear to be particularly sensitive to trabectedin, but the sensitivity of some rare STSs histological subtypes to the drug is rather unknown. We report on two patients suffering from infrequent subtypes of STSs, fibrosarcoma and epithelioid sarcoma, who were treated with trabectedin. In these cases the treatment completely failed, and right after the first cycle of trabectedin administration an unusually rapid tumor growth and dissemination was documented. Of note, one of the patients showed objective response to MVIP chemotherapy (methotrexate, etoposide, ifosfamide and cisplatin), after trabectedin failure. Trabectedin activity against several subtypes has not been studied or well-documented due to the rarity and numerous histotypes of STSs. Case studies aiming at the individualization of treatment options against specific STS subtypes will further justify the usage of this agent in clinical practice.

Fibrosarcomas (FS) of bone are a rare malignancy accounting for less than 5% of all primary malignant bone neoplasms. Diagnosis and treatment approaches of this entity are complex and require a skilled and experienced multidisciplinary team.Authors report their experience with a case of FS of humerus showing a pathologic complete response to neo-adjuvant chemotherapy based on adriamycin, cisplatin and ifosfamid. This approach allowed limb-sparing surgery with an excellent functional and psychological result.

Vascular disrupting agents (VDA) offer a strategy to starve solid tumors of nutrients and oxygen concomitant with tumor shrinkage. Several VDAs have progressed into early clinical trials, but their therapeutic value seems to be compromised by systemic toxicity. In this report, we describe the design and characterization of a novel VDA, ICT2588, that is nontoxic until activated specifically in the tumor by membrane-type 1 matrix metalloproteinase (MT1-MMP). HT1080 cancer cells expressing MT1-MMP were selectively chemosensitive to ICT2588, whereas MCF7 cells that did not express MT1-MMP were nonresponsive. Preferential hydrolysis of ICT2588 to its active metabolite (ICT2552) was observed in tumor homogenates of HT1080 relative to MCF7 homogenates, mouse plasma, and liver homogenate. ICT2588 activation was inhibited by the MMP inhibitor ilomastat. In HT1080 tumor-bearing mice, ICT2588 administration resulted in the formation of the active metabolite, diminution of tumor vasculature, and hemorrhagic necrosis of the tumor. The antitumor activity of ICT2588 was superior to its active metabolite, exhibiting reduced toxicity, improved therapeutic index, enhanced pharmacodynamic effect, and greater efficacy. Coadministration of ICT2588 with doxorubicin resulted in a significant antitumor response (22.6 d growth delay), which was superior to the administration of ICT2588 or doxorubicin as a single agent, including complete tumor regressions. Our findings support the clinical development of ICT2588, which achieves selective VDA targeting based on MT-MMP activation in the tumor microenvironment.

Radiation-induced midbrain fibrosarcoma is a rare, highly aggressive tumor, which is associated with poor prognosis. We present the case of a 48-year old man with brainstem fibrosarcoma 20 years following radiation therapy received for a pituitary tumor. We discuss this case in the context of the diagnostic criteria for these tumors, and previous reports of secondary and primary sarcomas of the central nervous system.

Matrix metalloproteinase (MMP) plays an important role in the invasion and metastasis of cancer cells. The inhibitory effects of bergamottin, a cytochrome P450 inhibitor from Citrus paradis (grapefruit), on tumor invasion and migration and the possible mechanisms involved in this inhibition were investigated in human fibrosarcoma HT-1080 cells. Bergamottin reduced phorbol-12-myristate-13-acetate (PMA)-induced activation of MMP-9 and MMP-2 and further inhibited cell invasion and migration. Bergamottin suppressed PMA-enhanced expression of MMP-9 protein, mRNA and transcription activity levels through suppression of nuclear factor-kappaB (NF-kappaB) activation without changing the tissue inhibitor of metalloproteinase 1 level. Bergamottin also reduced PMA-enhanced MMP-2 expression through suppression of membrane-type 1 MMP, but did not alter tissue inhibitor of metalloproteinase 2 levels. Bergamottin inhibited PMA-induced NF-kappaB nuclear translocation and IkappaBalpha degradation, which are upstream of PMA-induced MMP-9 expression and invasion. Furthermore, bergamottin strongly repressed the PMA-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK), which are dependent on the protein kinase C-delta pathway. In conclusion, we demonstrated that the anti-invasive effects of bergamottin might occur through inhibition of protein kinase C-delta, p38 mitogen-activated protein kinase, and JNK phosphorylation and reduction of NF-kappaB activation, leading to downregulation of MMP-9 expression. These results suggest that the suppression of MMP expression contributes, at least in part, to the antitumor activity of bergamottin.

Third-generation bisphosphonates are known to inhibit bone resorption and also appear to exhibit direct anti-tumour activity. We previously reported that third-generation bisphosphonates such as zoledronic acid (ZOL) have a direct antitumour effect, and synergistically augment the effects of antitumor agents in osteosarcoma cells. There has been no report on the antitumor effect of ZOL against soft tissue sarcoma. The aim of this study was to evaluate the antitumor effect of this drug on a human fibrosarcoma cell line, in terms of proliferation and apoptosis, and, moreover, to evaluate the combined effects of ZOL with other antitumor drugs against the human fibrosarcoma cell line. HT1080 cells were treated with ZOL at various concentrations up to 10 microM, and then cell proliferation, cell cycle, nuclear morphology, and Western blot analyses were performed to study the antitumor effects of ZOL alone, and, moreover, HT1080 cells were treated with ZOL and other anticancer drugs such as paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, cisplatin, or methotrexate to investigate the combined effects using proliferation and cell cycle analyses. We found that ZOL strongly inhibited in vitro proliferation, arrested the cell cycle between S and G2/M phases, and induced the apoptosis of human fibrosarcoma cells. Moreover, ZOL augmented the effect of antitumor agents when administered concurrently with paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, and cisplatin in human fibrosarcoma cells. The treatment of fibrosarcoma with ordinary antitumor drugs is not fully effective. These findings suggest that ZOL directly affects the proliferation and survival of fibrosarcoma cells, and that the combined administration of ZOL with other antitumor agents may improve the efficacy of fibrosarcoma treatment. These results support the possibility that their combined use could be beneficial in the treatment of patients not only with various types of cancer or osteosarcoma, but also with soft tissue sarcoma.

Electrochemotherapy is an efficient local treatment of tumors that combines administration of a chemotherapeutic drug with the subsequent application of electric pulses to the tumor. Although no difference in clinical response of the treated tumors to the electrochemotherapy when using 1 Hz or 5 kHz repetition frequency was observed, it is mandatory to be aware of possible differences in the effectiveness of electrochemotherapy when using suboptimal doses of the drugs. Therefore, this study compares the antitumor effectiveness of electrochemotherapy using electric pulse trains with repetition frequencies of 1 Hz and 5 kHz at suboptimal drug doses of bleomycin or cisplatin. Electrochemotherapy of fibrosarcoma SA-1 subcutaneous tumors transplanted in A/J mice resulted in good antitumor effectiveness, but antitumor effectiveness was significantly better at 1 Hz repetition frequency than at 5 kHz. The platinum content was higher in tumors treated with a 1 Hz repetition frequency. The application of electric pulses to the tumors at a 5 kHz repetition frequency induced an immediate reduction in tumor perfusion, comparable to the reduction at 1 Hz but with faster reperfusion. The greater effectiveness of electrochemotherapy using electric pulse trains of 1 Hz compared to 5 kHz is due to the greater electroporative effect and longer time in which electroporated tumors are exposed to the two chemotherapeutic drugs. These differences are observed at suboptimal drug doses, whereas at optimal drug doses of bleomycin or cisplatin the antitumor effectiveness is the same, as demonstrated in clinical trials.

Notch and Hedgehog activate cell-cycle progression of adult and cancer stem cells. Notch is activated by DLL and Jag presents on neighboring cells. We investigated the effects of density of the Notch-activating ligand, Jag-1, and targeting Gli-1, in activation of division of paclitaxel/taxol-resistant, (PTX Res) ovarian cancer cells SKOV3 (SKOV3). We used the specific gamma-presenilin inhibitor, DAPT, to identify the specificity of activating signals for Notch-1 and created 'butterfly-duplex-3548-Gli-1-inhibitory RNA' (i-Gli-1.RNA) to inhibit cell division. To accurately quantify kinetics of division, the expression of CD44 and CD24 was determined in each gated population of divided cells. CD44 High proliferated when activated by Jag-1 Low and poorly when activated by Jag-1 High. DAPT inhibited proliferation of cells activated by Jag-1 Low, and increased proliferation of cells activated by Jag-1 High. Only 5-10% of cells activated by Jag-1 High and Jag-1 Low divided fast, polynomial, and symmetric. i-Gli-1.RNA eliminated more than 50% of the small CD44 High/CD24 Neg cells in divisions 3 and 4. This effect appeared specific compared with cells transfected with negative control siRNA. i-Gli-1.RNA had no effect on large CD44 High/CD24 Neg cells, but inhibited the population of CD44 High/CD24 Low cells. Expansion of CD44 High inversely correlated with Jag-1 density on activating autologous tumor and fibrosarcoma cells. Created i-RNAs may decrease the resting CSC pool. Notch and Gli-1 signals play an important role in proliferation/division and survival of cancer stem cells. Targeting Notch-1 through its enhancer Gl-1, should be significant for novel treatments to eliminate taxol-resistant cancer stem cells (CSC). i.Gli-1 RNA should be more effective if used together with Taxol.

Singlet oxygen ((1)O(2)) is the major cytotoxic agent responsible for cell killing for type-II photodynamic therapy (PDT). An empirical four-parameter macroscopic model is proposed to calculate the "apparent reacted (1)O(2) concentration", [(1)O(2)](rx), as a clinical PDT dosimetry quantity. This model incorporates light diffusion equation and a set of PDT kinetics equations, which can be applied in any clinical treatment geometry. We demonstrate that by introducing a fitting quantity "apparent singlet oxygen threshold concentration" [(1)O(2)](rx, sd), it is feasible to determine the model parameters by fitting the computed [(1)O(2)](rx) to the Photofrin-mediated PDT-induced necrotic distance using interstitially-measured Photofrin concentration and optical properties within each mouse. After determining the model parameters and the [(1)O(2)](rx, sd), we expect to use this model as an explicit dosimetry to assess PDT treatment outcome for a specific photosensitizer in an in vivo environment. The results also provide evidence that the [(1)O(2)](rx), because it takes into account the oxygen consumption (or light fluence rate) effect, can be a better predictor of PDT outcome than the PDT dose defined as the energy absorbed by the photosensitizer, which is proportional to the product of photosensitizer concentration and light fluence., ((c) 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Today, green synthesis of nanoparticles is attracting increasing attention. In the present study, the Bacillus sp. MSh-1 was isolated from the Caspian Sea (located in the northern part of Iran) and identified by various identification tests and 16S ribosomal DNA analysis. The reduction time course study of selenium ion (Se(4+)) reduction by using this test strain was performed in a liquid culture broth. Then, the intracellular NPs (nanoparticles) were released by the liquid nitrogen disruption method and thoroughly purified using an n-octyl alcohol water extraction system. Characterization of the separated NPs on features such as particle shape, size and purity was carried out with different devices. The energy dispersive X-ray and X-ray diffraction patterns showed that the purified NPs consisted of only selenium and are amorphous respectively. In addition, the transmission electron micrograph showed that the separated NPs were spherical and 80-220 nm in size. Furthermore, the cytotoxicity effect of these extracted biogenic selenium (Se) NPs on the fibrosarcoma cell line (HT-1080) proliferation and the inhibitory effect of the Se NPs on MMP-2 (matrix metalloproteinase-2) expression were studied using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and gelatin zymography. Biogenic Se NPs showed a moderately inhibitory effect on MMP-2 expression.

Local recurrence of feline soft tissue sarcomas is common despite aggressive treatment. Liposomal doxorubicin might serve as a depot radiosensitizer if administered concomitantly with daily radiotherapy and thus improve tumor control. In this pilot study, the feasibility of concomitant liposomal radiochemotherapy was evaluated in a palliative setting in 10 cats with advanced soft tissue sarcomas. Cats were treated with median number of 5 (range 5-7) daily fractions of radiotherapy and a median total dose of 20 Gy (range 20-31.5 Gy). One dose of liposomal doxorubicin was administered at the beginning of radiotherapy. Seven cats received further free or liposomal doxorubicin after completion of the liposomal doxorubicin/radiation protocol. Seven of the treated 10 cats (70%) achieved a partial (n=5) or complete (n=2) response with a median response duration of 237 days. The median progression free interval in all 10 cats was 117 days and the median overall survival time was 324 days. Concomitant liposomal radiochemotherapy was tolerated well in nine cats, one cat experienced temporary anorexia. Although the number of patients is too small to make definitive conclusions, results appear promising enough to investigate the role of liposomal doxorubicin as a radiosensitizer further.

We sought to reduce tumor hypoxia by topical application of a vasodilator, benzyl nicotinate (BN), and investigated its effect on the growth of tumors irradiated at times when tumor pO(2) increased. EPR oximetry was used to follow the changes in the tissue pO(2) of subcutaneous radiation-induced fibrosarcoma (RIF-1) tumors during topical applications of 1.25-8% BN formulations for 5 consecutive days. The RIF-1 tumors were hypoxic with a tissue pO(2) of 4.6-7.0 mmHg. A significant increase in tumor pO(2) occurred 10-30 min after BN application. The formulation with the minimal BN concentration that produced a significant increase in tumor pO(2) was used for the radiation study. The tumors were irradiated (4 Gy x 5) at the time of the maximum increase in pO(2) observed with the 2.5% BN formulation. The tumors with an increase in pO(2) of greater than 2 mmHg from the baseline after application of BN on day 1 had a significant growth inhibition compared to the tumors with an increase in pO(2) of less than 2 mmHg. The results indicate that the irradiation of tumors at the time of an increase in pO(2) after the topical application of the 2.5% BN formulation led to a significant growth inhibition. EPR oximetry provided dynamic information on the changes in tumor pO(2), which could be used to identify responders and non-responders and schedule therapy during the experiments.

Fibrosarcoma has been defined as a malignant tumor of the fibroblasts that shows no other evidence of cellular differentiation and is capable of recurrence and metastasis. Fibrosarcomas are rare but may occur anywhere in the body, most commonly in the retroperitoneum, thigh, knee and distal extremities. Fibrosarcoma is uncommon in the head and neck region and constitutes about 1% of all the malignancies affecting the human race. Of all the fibrosarcomas occurring in humans, only 0.05% occurs in the head and neck region. Of this, almost 23% is seen in the oral cavity. Fibosarcomas generally have a poor prognosis and the overall survival rate is 20-35% over a period of 5 years.

A rare case of primary fibrosarcoma in a 48-year-old male is described who presented with a huge pulmonary mass on the left side. The diagnosis was established on fine needle aspiration cytology (FNAC) and percutaneous transthoracic lung biopsy, supported by immuno-histochemistry.

Purpose: Staphylococcal enterotoxin B (SEB) is a potent inducer of cytotoxic T-cell activity, cytokine production and necrosis induction in vivo. Monophosphoryl lipid A (MPL) is an adjuvant derived from the lipopolysaccharide of E. coli, Salmonella Minnesota Re595 and other gram negative bacteria. We investigated the possibility of the therapeutic application of SEB+ MPL in mice with fibrosarcoma., Methods: The antitumor effect of SEB+MPL, SEB and MPL in mice with inoculated fibrosarcoma tumor (WEHI-164) was examined by intravenous (i.v.) and intratumoral (i.t.) injection and the sizes of the inoculated tumors, IFN-gamma production, and CD4(+)/CD8(+) T cell infiltration were determined. The inoculated tumors were also examined histologically., Results: In the i.v.-injected group of mice with SEB+ MPL, reduction of tumor size showed a significant difference compared with mice in the i.t., the i.v. (MPL)-injected groups and the negative control group (p < 0.02). Moreover, the mice in the i.v. (SEB+ MPL)-injected group showed significantly higher levels of IFN-gamma (p < 0.009) and CD4(+)/CD8(+) T cell infiltration when compared with the other groups (p < 0.02). A significantly higher frequency of necrosis in tumor tissues was also observed in mice in the i.v. (SEB+ MPL)-injected group in comparison with other groups (p < 0.009)., Conclusion: Our findings suggest that tumor cell death is caused by increased cytotoxic T-cell activity, cytokine levels, in response to IV injection of SEB+MPL. They also suggest that tumor cell death by synergistic effect of one of the strongest bacterial superantigens (SEB) with monophosphoryl lipid A and SEB+MPL may be a good option for use as a novel therapy in patients with fibrosarcoma.

3-Bromoacetamino-4-methoxy-benzoylurea (F13) is a benzoylurea derivative selected from the library of small molecule tubulin ligands. Our earlier data showed that F13 had lost the capacity to interrupt microtubule dynamics while reserving anticancer activity. In this study, we found that F13 greatly inhibited cell proliferation in various human cancer cells. At concentrations of more than 1 microg/ml, F13 markedly slowed growth and induced apoptosis in HT-1080 cells. This apoptosis occurred through cleavages of caspase 3 and PARP. At low concentrations (< or =1 microg/ml), F13 reduced the migration, adhesion, and invasion of HT-1080 cells. In addition, F13 downregulated the activities of matrix metalloproteinase-2/9 (MMP-2/9) in a culture supernatant. This was found to occur through the upregulation of the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored inhibitor of MMPs, which acts by reducing ERK1/2 phosphorylation. Our data suggested that F13 might act as a novel RECK inducer, inhibiting cancerous processes with the inactivation of MMP-2/9 by the induction of RECK through the inhibition of ERK1/2 signalling transduction.

Congenital infantile fibrosarcoma (CIF) is a rare tumor in childhood. The 5-year survival rate for CIFs is high and has been reported between 84% and 93%, but limb-amputation/disarticulation is still a major problem. We report the case of a male newborn with a mass in his right foot. X-ray and MRI revealed a mass destroying all tarsal, metatarsal, and phalangeal bones. The patient was treated only with VAC chemotherapy and is able to walk normally.

The traditional treatments for fibrosarcoma have limited efficacy. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Accumulating evidence indicates that programmed cell death (PCD) is closely related to anticancer therapy. Many studies have shown that tumor cells treated with anticancer drugs experience the induction of type I PCD, apoptosis, and type II PCD, autophagy. In the present study, we investigated the anticancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) in human fibrosarcoma cells in vitro and in xenograft tumors in SCID mice in vivo. We found that IR increased the population of HT1080 cells in the G2/M phase in a time-dependent manner within 9 h. IR treatment combined with ATO at this time point induced a significantly prolonged G2/M arrest and consequently enhanced cell death. Furthermore, damage of mitochondria membrane potential could be involved in the underlying mechanisms. The enhanced cytotoxic effect of combined treatment occurred due to the increased induction of more autophagy and apoptosis through the inhibition of Akt and the activation of ERK1/2 signaling pathways in HT1080 cells. The combined treatment of HT1080 cells pretreated with Z-VAD or 3-MA resulted in a significant reduction in AO-positive cells, apoptotic cells and cytotoxicity. In in vivo studies, the combination of IR and ATO significantly reduced the tumor volume in SCID mice that had received a subcutaneous injection of HT1080 cells. The data suggest that a combination of IR and ATO could be a new potential therapeutic strategy for the treatment of fibrosarcoma.

Due to their unique properties, Anticancer dendrimer-based drugs have been displaying promising results in both in vitro and in vivo in the treatment of cancerous cells, as compared to the traditional polymers. In this report, two conjugates (G1+Pt and G2+Pt) of cisplatin [cis-diaminedichloroplatinum; (CDDP)] with two generations (G1, G2) of a biocompatible anionic dendrimer were prepared in an aqueous media. Their potential cytotoxic effects, in two sensitive cancer cell lines HT1080 and CT26 together with one resistant cancer cell line SKOV3, using MTT (methyl thiazolyl tetrazolium) assay were examined. Hemolytic impacts and cell death mechanisms of the conjugates on human blood and HT1080 cell line were also investigated. The conjugate G2+Pt showed greater toxicity up to 9x and 2x in the sensitive and resistant cell lines (IC(50) comparison, inhibitory concentration) respectively when compared to the parent drug. The G1+Pt conjugate showed greater toxicity only in the sensitive HT1080 (2x) and CT26 (3.7x) cell lines. Moreover, the G1+Pt conjugate was less toxic approximately one third of the cisplatin in SKOV3 after 48 hrs of incubation. In summary, the G2+Pt conjugate had greater toxicity than the G1+Pt conjugate and cisplatin, based on the in vitro results. Approximately the same hemolysis behavior was observed for both conjugates and cisplatin. Both apoptosis and necrosis mechanisms (about 2x more than cisplatin) were attributed to conjugates and cisplatin in a direct correlation between the concentration and the degree of cell death. In conclusion, these conjugates with such high potency and minimum hemolysis would be suitable candidates for use against these cancerous cell lines as efficient and novel antitumor agents.

It has been demonstrated that inadequate dispersion of cancer chemotherapeutic drugs throughout the tissues of larger, relatively poorly vascularised tumours compromises the therapeutic effectiveness of such drugs. Recently we demonstrated that electric fields could be exploited to achieve dispersion of a cancer chemotherapeutic drug through relatively impermeable tissues of a poorly vascularised solid tumour model. Using a modified Sonidel SP100 sonoporator we demonstrate that ultrasound may enhance the toxicity of a cancer chemotherapeutic drug by dispersing the drug through relatively impermeable tissues of a non-vascularised tumour model in vivo. We suggest that such a phenomenon may play a significant role in ultrasound targeting of cancer chemotherapeutic drugs, particularly in the treatment of solid tumours., (Crown Copyright 2009. Published by Elsevier Ireland Ltd. All rights reserved.)

Paclitaxel (PTX) is a highly effective cytotoxic agent widely used for the treatment of several solid tumors. However, PTX shows dose-limiting cytotoxicity and in most cases induces drug resistance followed by failure in treatment. To enhance the therapeutic index of a given drug, various drug delivery methods have been explored to systemically deliver sufficient amount of the drug to the desired site. In the present study, we designed and synthesized two PTX prodrugs by conjugating PTX at different sites with an octapeptide (AcGPLGIAGQ) that can be cleaved by MMP2 at tumor sites. As a result, PTX is expected to be released at the tumor sites, absorbed by the tumor cells, and thereby inhibit the tumor growth. We evaluated the in vitro activities of the two drugs in a panel of drug-sensitive and -resistant cancer cell lines and their in vivo efficacies in a HT1080 fibrosarcoma mouse xenograft model that overexpresses MMP2. Our in vitro results showed that the PTX-AcGPLGIAGQ conjugates inhibited cancer cell proliferation with higher activity compared to that observed for free PTX, both of which were mediated by an arrest of G(2)/M-phase of the cell cycle. Consistent with the in vitro results, treatment with PTX-octapeptide conjugate resulted in extensive areas of necrosis and a lower percentage of proliferating cells in xenograft tumor sections. Together, our results indicate the potential of the tumor-targeted delivery of PTX to exploit the specific recognition of MMP2, reduce toxicity, and selectively kill tumor cells.

Purpose: To retrospectively analyze the clinical features and results of treatment in 56 infants with fibrosarcoma enrolled onto cooperative European protocols between 1979 and 2005 and treated with a combination of surgery and chemotherapy., Patients and Methods: We performed a retrospective case review of infants under the age of 2 years with fibrosarcoma treated between 1979 and 2005 in six European studies. Patients were staged according to the Intergroup Rhabdomyosarcoma Staging System international classification as a function of the type of initial surgery and the extent of disease and were treated with surgery and chemotherapy. Survival was calculated using the Kaplan-Meier method., Results: Primary tumor site was the limbs in 66% of patients; median tumor diameter was more than 5 cm in 63% of patients; and postoperative staging was as follows: group I, 22%; group II, 27%; group III, 47%; and group IV, 4%. Response rate to chemotherapy was 75%, and the specific response rate to vincristine-dactinomycin was 71%. Local control was obtained in 84% of patients. At the end of follow-up, 45% of survivors had been treated by surgery alone, 6% by chemotherapy alone, 46% by surgery and chemotherapy, and 2% by surgery, chemotherapy, and radiotherapy. The 5-year overall survival (OS) rate was 89%. The 5-year OS and event-free survival rates for localized patients were 89% and 81%, respectively., Conclusion: Although complete resection is rarely feasible at diagnosis, conservative surgery remains the mainstay treatment for infantile fibrosarcoma. An alkylating agent-free and anthracycline-free regimen is usually effective and should be chosen as first-line chemotherapy for inoperable tumors. Overall prognosis is good, but progression or relapse, mainly local, remains possible.

Infantile fibrosarcoma represents less than 1% of all childhood cancers, but it is the most common soft-tissue sarcoma in those under 1 year of age. We report an infant with congenital infantile fibrosarcoma diagnosed as hemangiopericytoma. He was treated with chemotherapy and extremity-sparing surgery. Amputation was avoided.

Conformationally constrained mimetics of the laminin cell-adhesion site, YIGSR, are described. The site is the natural antagonist of the integrin-associated laminin receptor 1 (LAMR1) known to mediate metastatic tumor adhesion. The attachment of selected metastatic cell lines toward the constrained antagonists has been assessed. Observed differential responses prompted by folding preferences of the mimetics revealed stronger attachment activities for turnlike structures. The results permit the conformational design of antimetastatic disintegrins.