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Tumor Models (tumor + models)
Selected AbstractsNew developments in small molecules targeting p53 pathways in anticancer therapyDRUG DEVELOPMENT RESEARCH, Issue 6 2008Chit Fang Cheok Abstract The tumor suppressor p53 is frequently inactivated in a wide variety of cancers and point mutations or deletions of the p53 gene are associated with poor prognosis in cancer. About half of all human tumors carry wildtype p53 but p53 wildtype functions are often suppressed by the overexpression of murine double minute 2 (MDM2), a negative regulator of p53. Restoration of p53 functions in tumor cells, therefore, represents an attractive strategy in combating cancer and has been the focus of intensive anticancer drug discovery. One strategy is to antagonize MDM2 functions and initial success was demonstrated in vitro and in xenograft tumor models using newly discovered small molecule inhibitors and antisense oligonucleotides. The new discovery of a compound targeting SirT1 (a member of the sirtuin family) in a p53-dependent reporter screen highlighted the importance of another negative regulator of p53 and offers an additional avenue for drug discovery and research on p53-activating therapeutics. Here, we discuss the developments of p53-activating small molecules and their potential use in combination therapy with established chemotherapeutics. These small molecules were discovered from chemical library screening using biochemical assays or cellular-based assays, and/or structure-based rational drug design strategies. Drug Dev Res 69:289,296, 2008. © 2008 Wiley-Liss, Inc. [source] Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4, gene,HEPATOLOGY, Issue 5 2008Chuan Yin Previous studies have shown that hepatocyte nuclear factor-4, (HNF4,) is a central regulator of differentiated hepatocyte phenotype and forced expression of HNF4, could promote reversion of tumors toward a less invasive phenotype. However, the effect of HNF4, on cancer stem cells (CSCs) and the treatment of hepatocellular carcinoma (HCC) with HNF4, have not been reported. In this study, an adenovirus-mediated gene delivery system, which could efficiently transfer and express HNF4,, was generated to determine its effect on hepatoma cells (Hep3B and HepG2) in vitro and investigate the anti-tumor effect of HNF4, in mice. Our results demonstrated that forced re-expression of HNF4, induced the differentiation of hepatoma cells into hepatocytes, dramatically decreased "stemness" gene expression and the percentage of CD133+ and CD90+ cells, which are considered as cancer stem cells in HCC. Meanwhile, HNF4, reduced cell viability through inducing apparent apoptosis in Hep3B, while it induced cell cycle arrest and cellular senescence in HepG2. Moreover, infection of hepatoma cells by HNF4, abolished their tumorigenesis in mice. Most interestingly, systemic administration of adenovirus carrying the HNF4, gene protected mice from liver metastatic tumor formation, and intratumoral injection of HNF4, also displayed significant antitumor effects on transplanted tumor models. Conclusion: The striking suppression effect of HNF4, on tumorigenesis and tumor development is attained by inducing the differentiation of hepatoma cells,especially CSCs,into mature hepatocytes, suggesting that differentiation therapy with HNF4, may be an effective treatment for HCC patients. Our study also implies that differentiation therapy may present as one of the best strategies for cancer treatment through the induction of cell differentiation by key transcription factors. (HEPATOLOGY 2008.) [source] Glioblastoma cells incorporate into tumor vasculature and contribute to vascular radioresistanceINTERNATIONAL JOURNAL OF CANCER, Issue 9 2010Candice A. Shaifer Abstract Glioblastoma multiforme (GBM) remains the most devastating neoplasm of the central nervous system and has a dismal prognosis. Ionizing radiation represents an effective therapy for GBM, but radiotherapy remains only palliative because of radioresistance. In this study, we demonstrate that glioma cells participate in tumor vascularization and contribute to vascular radioresistance. Using a 3-dimensional coculture system, we observed an intimate interaction of glioma cells with endothelial cells whereby endothelial cells form vascular structures, followed by the recruitment and vascular patterning of glioma cells. In addition, tumor cells stabilize the vascular structures and render them radioresistant. Blocking initial endothelial vascular formation with endothelial-specific inhibitors prevented tumor cells from forming any structures. However, these inhibitors exhibited minimum effects on vascular structures formed by tumor cells, due to the absence of the targeted receptors on tumor cells. Consistent with the in vitro findings, we show that glioma cells form perfused blood vessels in xenograft tumor models. Together, these data suggest that glioma cells mimic endothelial cells and incorporate into tumor vasculature, which may contribute to radioresistance observed in GBM. Therefore, interventions aimed at the glioma vasculature should take into consideration the chimeric nature of the tumor vasculature. [source] Analysis of Aurora-A and hMPS1 mitotic kinases in mantle cell lymphomaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Emma Camacho Abstract Aurora-A and hMPS1 are kinases involved in spindle checkpoint and centrosome duplication regulation and whose alterations have been associated with cell transformation and chromosome instability in different tumor models. In this study, we have examined the possible alterations of these genes in 58 mantle cell lymphomas (MCLs) and 4 MCL-related cell lines. Aurora-A was also examined in 46 diffuse large B-cell lymphomas (DLBCLs). Aurora-A and hMPS1 mRNA expression levels were related to tumor proliferative activity. Interestingly, a MCL case with the highest number or chromosomal imbalances also showed an extremely high value of Aurora-A mRNA expression. No Aurora-A gene amplifications were detected in any tumor or cell line, whereas hemizygous hMPS1 gene deletions were observed in 23% of MCLs and 3 of the 4 cell lines. However, no expression alterations or gene mutations were detected in these cases. The Aurora-A proposed cancer susceptibility polymorphic variant (P31I) was observed with a similar frequency in MCL, DLBCL, chronic lymphocytic leukemia and in the 431 healthy controls. However, the 3 MCLs and 4 DLBCLs with the homozygous variant of this polymorphism had particular clinical characteristics with an unusual early-age presentation and second epithelial malignancies in MCL and extranodal origin in DLBCL. These findings indicate that Aurora-A and hMPS1 aberrations are uncommon in aggressive lymphomas but Aurora-A overexpression may contribute to numerical chromosomal alterations in occasional MCL. Although the Aurora-A P31I polymorphic variant is not directly involved in a genetic predisposition to these lymphomas, it may modulate the clinical presentation of these tumors. © 2005 Wiley-Liss, Inc. [source] Enhanced efficacy of DNA vaccination against Her-2/neu tumor antigen by genetic adjuvantsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Sun Young Chang Abstract Certain types of malignant tumors overexpress Her-2/neu, a transmembrane glycoprotein of the class I receptor tyrosine kinase erbB family. To develop an effective Her-2/neu vaccine for selective immunotherapy of these malignancies, we prepared Her-2/neu DNA plasmid encoding the transmembrane and extracellular domain (pHM) and tested the ability of this construct to induce antitumor immunity in animal models. In addition, we investigated the effects of cytokine used as a genetic adjuvant. Modulation by factors that affect T-cell function or hematopoiesis, including interleukin-12, interleukin-15, interleukin-18, interleukin-23, Eta-1, Flt3L and GM-CSF, was studied in the forms of monocistronic and bicistronic plasmid. Our results demonstrated that vaccination of pHM could induce successful antitumor immunity against Her-2/neu-expressing murine tumor cells in BALB/c mice. We also showed that the antitumor activity of pHM was augmented by coadministration and coexpression of different cytokines. Despite the similar levels of gene expression, the antitumor effects of bicistronic plasmids coexpressing Her-2/neu antigen and cytokine were improved in comparison with coadministration of separate monocistronic plasmid. In particular, coexpression of interleukin-18 or GM-CSF with Her-2/neu increased antitumor activity in both preventive and therapeutic experiments. These findings can help in the decision concerning which of the various cytokine adjuvants should be used for the development of a Her-2/neu DNA vaccine. In addition, our results from a large panel of cytokine adjuvants in the various tumor models may provide an insight into the important immune components of antitumor immunity. © 2004 Wiley-Liss, Inc. [source] Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2003G. J. Brewer Abstract The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines. [source] Pro-metastasis function of TGF, mediated by the smad pathwayJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2006Yibin Kang Abstract The transforming growth factor beta (TGF,) signaling pathway plays a vital role in the development and homeostasis of normal tissues. Abnormal function of this pathway contributes to the initiation and progression of cancer. Smad proteins are key signal transducers of the TGF, pathway and are essential for the growth suppression function of TGF,. Smads are bona fide tumor suppressors whose mutation, deletion, and silencing are associated with many types of human cancer. However, the involvement and functional mechanism of Smad proteins in cancer metastasis are poorly defined. Recent studies using genetically modified cancer cells and mouse tumor models have provided concrete evidence for a Smad-dependent mechanism for metastasis promotion by TGF,. Understanding the dual roles of Smad proteins in tumor initiation and progression has important implications for cancer therapeutics. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] Tumor R2* is a prognostic indicator of acute radiotherapeutic response in rodent tumorsJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 4 2004Loreta M. Rodrigues MSc Abstract Purpose To test the prognostic potential of tumor R2* with respect to radiotherapeutic outcome. Blood oxygenation level dependent (BOLD) MRI images are sensitive to changes in deoxyhemoglobin concentration through the transverse MRI relaxation rate R2* of tissue water, hence the quantitative measurement of tumor R2* may be related to tissue oxygenation. Methods and Materials Tumor growth inhibition in response to radiation was established for both GH3 prolactinomas and RIF-1 fibrosarcomas with animals breathing either air or carbogen during radiation. In a separate cohort, the baseline R2* and carbogen (95% O2, 5% CO2)-induced ,R2* of rat GH3 prolactinomas and murine RIF-1 fibrosarcomas were quantified using multigradient echo (MGRE) MRI prior to radiotherapy, and correlated with subsequent tumor growth inhibition in response to ionizing radiation, while the animals breathed air. Results A radiation dose of 15 Gy caused pronounced growth delay in both tumor models and transient regression of the GH3 prolactinomas. When the animals breathed carbogen during radiation, the growth delay/regression was enhanced only in the GH3 prolactinomas. The GH3 prolactinomas, which exhibit a relatively fast baseline R2* and large ,R2* in response to carbogen breathing prior to radiotherapy, showed a substantial reduction in normalized tumor volume to 66 ± 3% with air breathing and 36 ± 5% with carbogen seven days after 15 Gy irradiation. In contrast, the effect of 15 Gy on the RIF-1 fibrosarcomas, which give a relatively slow baseline R2* and negligible ,R2* response to carbogen prior to treatment, showed a much smaller growth inhibition (143 ± 3% with air, 133 ± 12% with carbogen). Conclusion Quantitation of tumor R2* and carbogen-induced ,R2* by MGRE MRI provides completely noninvasive prognostic indicators of a potential acute radiotherapeutic response. J. Magn. Reson. Imaging 2004;19:482,488. © 2004 Wiley-Liss, Inc. [source] Cytotoxicity and apoptosis enhancement in brain tumor cells upon coadministration of paclitaxel and ceramide in nanoemulsion formulationsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2008Ankita Desai Abstract The objective of this study was to examine augmentation of therapeutic activity in human glioblastoma cells with combination of paclitaxel (PTX) and the apoptotic signaling molecule, C6 -ceramide (CER), when administered in novel oil-in-water nanoemulsions. The nanoemulsions were formulated with pine-nut oil, which has high concentrations of essential polyunsaturated fatty acid (PUFA). Drug-containing nanoemulsions were characterized for particle size, surface charge, and the particle morphology was examined with transmission electron microscopy (TEM). Epi-fluorescent microscopy was used to analyze nanoemulsion-encapsulated rhodamine-labeled PTX and NBD-labeled CER uptake and distribution in U-118 human glioblastoma cells. Cell viability was assessed with the MTS (formazan) assay, while apoptotic activity of PTX and CER was evaluated with caspase-3/7 activation and flow cytometry. Nanoemulsion formulations with the oil droplet size of approximately 200 nm in diameter were prepared with PTX, CER, and combination of the two agents. When administered to U-118 cells, significant enhancement in cytotoxicity was observed with combination of PTX and CER as compared to administration of individual agents. The increase in cytotoxicity correlated with enhancement in apoptotic activity in cells treated with combination of PTX and CER. The results of these studies show that oil-in-water nanoemulsions can be designed with combination therapy for enhancement of cytotoxic effect in brain tumor cells. In addition, PTX and CER can be used together to augment therapeutic activity, especially in aggressive tumor models such as glioblastoma. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2745,2756, 2008 [source] Noncompartmental kinetic analysis of DCE-MRI data from malignant tumors: Application to glioblastoma treated with bevacizumabMAGNETIC RESONANCE IN MEDICINE, Issue 2 2010Ruediger E. Port Abstract Dynamic contrast enhanced MRI contrast agent kinetics in malignant tumors are typically complex, requiring multicompartment tumor models for adequate description. For consistent comparisons among tumors or among successive studies of the same tumor, we propose to estimate the total contrast agent,accessible volume fraction of tumor, including blood plasma, vpe, and an average transfer rate constant across all tumor compartments, Ktrans.av, by fitting a three-compartment tumor model and then calculating the area under the tumor impulse-response function (= vpe) and the ratio area under the tumor impulse response function over mean residence time in tumor (= Ktrans.av). If the duration of dynamic contrast enhanced MRI was too short to extrapolate the tumor impulse-response function to infinity with any confidence, then conditional parameters v and Ktrans.av* should be calculated from the available incomplete impulse response function. Median decreases of 33% were found for both v and Ktrans.av* in glioblastoma patients (n = 16) 24 hours after the administration of bevacizumab (P < 0.001). Median total contrast-enhancing tumor volume was reduced by 18% (P < 0.0001). The combined changes of tumor volume, v, and Ktrans.av* suggest a reduction of true vpe, possibly accompanied by a reduction of true Ktrans.av. The proposed method provides estimates of a scale and a shape parameter to describe contrast agent kinetics of varying complexity in a uniform way. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc. [source] 2D and 3D radial multi-gradient-echo DCE MRI in murine tumor models with dynamic R*2 -corrected R1 mappingMAGNETIC RESONANCE IN MEDICINE, Issue 1 2010Julien Vautier Abstract Dynamic contrast-enhanced MRI is extensively studied to define and evaluate biomarkers for early assessment of vasculature-targeting therapies. In this study, two-dimensional and three-dimensional radial multi-gradient-echo techniques for dynamic R*2 -corrected R1 mapping based on the spoiled gradient recalled signal equation were implemented and validated at 4.7 T. The techniques were evaluated on phantoms and on a respiratory motion animated tumor model. R1 measurements were validated with respect to a standard inversion-recovery spin-echo sequence in a four-compartment phantom covering a range of relaxation rates typically found in tumor tissue. In the range of [0.4, 3] sec,1, R1 differences were less than 10% for both two-dimensional and three-dimensional experiments. A dynamic contrast-enhanced MRI pilot study was performed on a colorectal tumor model subcutaneously implanted in mice at the abdominal level. Low motion sensitivity of radial acquisition allowed image recording without respiratory triggering. Three-dimensional Ktrans maps and significantly different mean Ktrans values were obtained for two contrast agents with different molecular weights. The radial multi-gradient-echo approach should be most useful for preclinical experimental conditions where the tissue of interest experiences physiologic motion, like spontaneous extracerebral tumors developed by transgenic mice, and where dynamic contrast-enhanced MRI is performed with high-relaxivity contrast agents. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc. [source] Statins can modulate effectiveness of antitumor therapeutic modalitiesMEDICINAL RESEARCH REVIEWS, Issue 1 2010Marek Jakobisiak Abstract Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents. However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation of these interactions might affect the choice of treatment to be planned in cancer patients as some combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a cost of increased general toxicity. Some other combinations might induce either comparable or even stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical relevance of the findings is also discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 1, 102,135, 2010 [source] Tyrosine kinase inhibitors: From rational design to clinical trialsMEDICINAL RESEARCH REVIEWS, Issue 6 2001Peter Traxler Abstract Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,- d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (GlivecÔ, GleevecÔ), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 6, 499,512, 2001 [source] Assessment of blood volume, vessel size, and the expression of angiogenic factors in two rat glioma models: a longitudinal in vivo and ex vivo studyNMR IN BIOMEDICINE, Issue 10 2008Samuel Valable Abstract Assessment of angiogenesis may help to determine tumor grade and therapy follow-up. In vivo imaging methods for non-invasively monitoring microvasculature evolution are therefore of major interest for tumor management. MRI evaluation of blood volume fraction (BVf) and vessel size index (VSI) was applied to assess the evolution of tumor microvasculature in two rat models of glioma (C6 and RG2). The results show that repeated MRI of BVf and VSI , which involves repeated injection of an iron-based MR contrast agent , does not affect either the physiological status of the animals or the accuracy of the MR estimates of the microvascular parameters. The MR measurements were found to correlate well with those obtained from histology. They indicate that microvascular evolution differs significantly between the two glioma models, in good agreement with expression of angiogenic factors (vascular endothelial growth factor, angiopoietin-2) and with activities of matrix metalloproteinases, also assessed in this study. These MRI methods thus provide considerable potential for assessing the response of gliomas to anti-angiogenic and anti-vascular agents, in preclinical studies as well as in the clinic. Furthermore, as differences between the fate of tumor microvasculature may underlie differences in therapeutic response, there is a need for preclinical study of several tumor models. Copyright © 2008 John Wiley & Sons, Ltd. [source] Diffusion tensor MRI in rat models of invasive and well-demarcated brain tumorsNMR IN BIOMEDICINE, Issue 3 2008Sungheon Kim Abstract Diffusion tensor imaging (DTI) and its metrics, such as mean diffusivity (MD) and fractional anisotropy (FA), have been used to detect the extent of brain tumors and understand tumor growth and its influence on the surrounding tissue. However, there are conflicting reports on how DTI metrics can be used for tumor diagnosis. The physiological interpretation of these metrics in terms of tumor growth is also not clear. The objective of this study was to investigate the DTI parameters in two rat brain tumor models (9L and F98) with different patterns of aggressiveness by longitudinal monitoring of tumor growth and comparing the DTI parameters of these two tumor models. In addition to the standard DTI metrics, MD and FA, we measured other metrics representing diffusion tensor shape, such as linear and planar anisotropy coefficients (CL and CP), and orientational coherence measured by lattice index (LI), to characterize the two tumor models. The 9L tumor had higher FA, CL, and LI than the F98 tumor. F98 had a larger difference in anisotropies between tumor and peritumor regions than 9L. From the eigenvalues, it was found that the increase in CL and trace of the 9L tumor was due to an increase in the primary eigenvalue, whereas the increase in CP in the peritumor region was due to an increase in both primary and secondary eigenvalues and a decrease in tertiary eigenvalue. Our results indicate that shape-oriented anisotropy measures, such as CL and CP, and orientational coherence measures, such as LI, can provide useful information in differentiating these two tumor models and also differentiating tumor from peritumoral regions. Copyright © 2007 John Wiley & Sons, Ltd. [source] Initial testing of the aurora kinase a inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP),PEDIATRIC BLOOD & CANCER, Issue 1 2010John M. Maris MD Abstract Background MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis. Procedures MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0,nM to 10,µM and was tested against the PPTP in vivo panels at a dose of 20,mg/kg administered orally twice daily,×,5 days. Treatment duration was 6 weeks for solid tumor xenografts and 3 weeks for ALL xenografts. Results MLN8237 had a median IC50 of 61,nM against the PPTP in vitro panel. The ALL cell lines were more sensitive and the rhabdomyosarcoma cell lines less sensitive than the remaining PPTP cell lines. In vivo, MLN8237 induced significant differences in event-free survival (EFS) distributions compared to controls in 32/40 (80%) solid tumor models and all (6/6) ALL models. Maintained complete responses (CRs) were observed in 3 of 7 neuroblastoma xenografts, and all 6 evaluable ALL xenografts achieved CR (n,=,4) or maintained CR (n,=,2) status. Maintained CRs were observed among single xenografts in other panels, including the Wilms tumor, rhabdoid tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and medulloblastoma. Conclusions The in vivo activity observed against the neuroblastoma panel far exceeds that observed for standard agents evaluated against the panel by the PPTP. High levels of in vivo activity were also observed against the ALL xenograft panel. These data support expedited clinical development of MLN8237 in childhood cancer. Pediatr Blood Cancer 2010;55:26,34. © 2010 Wiley-Liss, Inc. [source] Initial testing of topotecan by the pediatric preclinical testing program,PEDIATRIC BLOOD & CANCER, Issue 5 2010Hernan Carol PhD Abstract Background Topotecan is a small molecule DNA topoisomerase I poison, that has been successful in clinical trials against pediatric solid tumors and leukemias. Topotecan was evaluated against the Pediatric Preclinical Testing Program (PPTP) tumor panels as part of a validation process for these preclinical models. Procedures In vivo three measures of antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models, or ,25% human CD45+ cells in the peripheral blood for acute lymphoblastic leukemia, ALL models) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Results Topotecan inhibited cell growth in vitro with IC50 values between 0.71 and 489,nM. Topotecan significantly increased EFS in 32 of 37 (87%) solid tumor xenografts and in all 8 of the ALL xenografts. Seventy-five percent of solid tumors met EFS T/C activity criteria for intermediate (n,=,17) or high activity (n,=,7). Objective responses were noted in eight solid tumor xenografts (Wilms, rhabdomyosarcoma, Ewing sarcoma, neuroblastoma). Among the six neuroblastomas, three achieved a PR. For the ALL panel, two maintained CRs, three CRs, and two PRs were observed. Conclusions Topotecan demonstrated broad activity in vitro and in vivo against both the solid tumor and ALL panels, with significant tumor growth delay generated in all the panels. These results further demonstrate the validity of the PPTP panel for preclinical testing of new drugs. Pediatr Blood Cancer 2010;54:707,715. © 2009 Wiley-Liss, Inc. [source] Initial testing of cisplatin by the pediatric preclinical testing program,PEDIATRIC BLOOD & CANCER, Issue 5 2008Mimi Tajbakhsh BS Abstract Background Cisplatin is one of the most widely used drugs for the treatment of solid tumors in adults and children. Here, we report the activity of cisplatin against the PPTP panels of childhood cancer xenografts. Procedures Cisplatin was evaluated against 23 cell lines, and 40 xenografts representing brain tumors, neuroblastoma, rhabdoid tumors, sarcoma, Wilms tumor, and acute lymphoblastic leukemia (ALL). The IC50 concentration in vitro was determined for 96 hr exposure. Solid tumors were grown subcutaneously in immune-deficient mice, and tumor dimensions measured weekly. ALL xenografts were inoculated intravenously and the percent human CD45+ cells in the peripheral blood determined weekly. The antitumor activity of cisplatin (7 mg/kg administered intraperitoneally on Days 0 and 21) was evaluated using time to event (EFS T/C), tumor growth delay (tumor volume T/C), and objective response measures. Results The median IC50 concentration in vitro was 0.87 µM (0.24,4.29 µM), and cisplatin exhibited broad range activity. Cisplatin induced significant differences in EFS distributions compared to controls in 20/28 solid tumors and 4/8 ALL models. Objective responses were observed in 7/28 solid tumor models (25%): partial responses in three rhabdomyosarcomas and one Ewing's sarcoma; complete responses in one rhabdoid tumor and the medulloblastoma; and a maintained complete response in one Wilms tumor. No objective responses were observed in the ALL panel. Conclusions Cisplatin exhibits significant antitumor activity against a broad range of solid tumor xenograft models and limited activity against ALL xenografts. This preclinical pattern of activity is generally consistent with cisplatin's clinical activity. Pediatr Blood Cancer 2008;50:992,1000. © 2007 Wiley-Liss, Inc. [source] The pediatric preclinical testing program: Description of models and early testing results,PEDIATRIC BLOOD & CANCER, Issue 7 2007Peter J. Houghton PhD Abstract Background The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. Procedures Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. Results Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. Conclusions We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity. Pediatr Blood Cancer 2007;49:928,940. Published 2006 Wiley-Liss, Inc. [source] Antivascular Tumor Eradication by Hypericin-mediated Photodynamic Therapy,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2002Bin Chen ABSTRACT Photodynamic therapy (PDT) with hypericin has been shown to inhibit tumor growth in different tumor models, and tumor vascular damage was suggested to be mainly responsible for the antitumoral effect. Here, we demonstrate tumor vascular damage and its consequence on local tumor control after hypericin-mediated PDT by using both short and long drug,light intervals. Radiation-induced fibrosarcoma-1 tumors were exposed to laser light at either 0.5 or 6 h after a 5 mg/kg dose of hypericin. Tumor perfusion was monitored by fluorescein dye,exclusion assay and by Hoechst 33342 staining of functional blood vessels. Significant reduction in tumor perfusion was found immediately after both PDT treatments. A complete arrest of vascular perfusion was detected by 15 h after the 0.5 h-interval PDT, whereas well-perfused areas could still be found at this time in tumors after the 6 h-interval PDT. A histological study confirmed that primary vascular damage was involved in both PDT treatments. Tumor cells appeared intact shortly after light treatment, degenerated at later hours and became extensively pycnotic at 24 h after the 0.5 h-interval PDT. PDT under this condition led to complete tumor cure. In contrast, significant numbers of viable tumor cells, especially at the tumor periphery, were found histologically at 24 h after the 6 h-interval PDT. No tumor cure was obtained when PDT was performed at this time. Our results strongly suggest that targeting the tumor vasculature by applying short drug,light interval PDT with hypericin might be a promising way to eradicate solid tumors. [source] In Vivo Pharmacokinetics of ,-Aminolevulinic Acid,Induced Protoporphyrin IX During Pre- and Post-Photodynamic Therapy in 7,12-Dimethylbenz(a)nthracene-Treated Skin Carcinogenesis in Swiss Mice: A Comparison by Three-Compartment Model,,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2002Parmeswaran Diagaradjane ABSTRACT ,-Aminolevulinic acid,photodynamic therapy (ALA-PDT) has emerged as a useful technique in the treatment of superficial basal cell carcinoma, actinic keratosis, squamous cell carcinoma and tumors of other organs. Earlier reports mention that there is reappearance of protoporphyrin IX (PpIX) after photoirradiation of tumors. This property of reappearance of PpIX is being utilized to treat nodular tumors by fractionated light dose delivery. However, there is still no unanimously accepted reason for this reappearance phenomenon and the rate of resynthesis after PDT. On account of this, studies are carried out on the estimation of the pharmacokinetics of the ALA-induced PpIX in mice tumor models and the surrounding normal tissues before and after PDT. Further, a mathematical model based on a multiple compartment system is proposed to estimate the rate parameter for the diffusion of PpIX from the surrounding normal tissues into the tumor tissue (km) caused by photobleaching during PDT with irradiating fluences of 36.0 and 57.6 J/cm2. The km value at two different fluences, 36.0 and 57.6 J/cm2, are estimated as 3.0636 ± 0.7083 h,1 and 6.9231 ± 2.17651 h,1, respectively. Further, the rate parameter for the cleavage and efflux of ALA (k1) and the rate parameter for the evasion of PpIX from the tumor tissues after PDT (kt) were also estimated by fitting the experimental data to the developed mathematical model. The statistical significance of the estimated parameters was determined using Student's t -test. The experimental results and the rate parameters obtained using the proposed compartment model suggest that in addition to the earlier reported reasons, the invasion or diffusion of PpIX from the surrounding tissues to the tumor tissues after photoirradiation might also contribute to the reappearance of PpIX after PDT. [source] A 2-DE MALDI-TOF study to identify disease regulated serum proteins in lung cancer of c-myc transgenic micePROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2009Bijon Chatterji Abstract We previously reported targeted overexpression of c-myc to alveolar epithelium to cause lung cancer. We now extended our studies to the serum proteome of tumor bearing mice. Proteins were extracted with a thiourea-containing lysis buffer and separated by 2-DE at pH,4,7 and 3,10 followed by MALDI-TOF/TOF analysis. Forty-six proteins were identified in tumor bearing mice of which n,=,9 were statistically significant. This included disease regulated expression of orosomucoid-8, ,-2-macroglobulin, apolipoprotein-A1, apolipoprotein-C3, glutathione peroxidase-3, plasma retinol-binding protein, and transthyretin, while expression of apolipoprotein-E was decreased at late stages of disease. Moreover, serum amyloid P component was uniquely expressed at late stages of cancer. It is of considerable importance that most disease regulated proteins carried the E-Box sequence (CACGTG) in the promoter of the coding gene, therefore providing evidence for their regulation by c-myc. Notably, expression of ,-2-macroglobulin, transthyretin, ,-1-antitrypsin, and properdin was in common in different lung tumor models, but regulation of orosomucoid-8, apolipoprotein-A1, apolipoprotein-C3, apolipoprotein-E, glutathione peroxidase-3, plasma retinol-binding protein, and serum amyloid P component was unique when the serum proteomes of c-myc and c-raf tumor bearing mice were compared. Therefore, candidate biomarkers to differentiate between atypical adenomatous hyperplasias (AAH) and bronchiolo-alveolar carcinomas (BAC)/papillary adenocarcinomas (PLAC) can be proposed. [source] Comparative analysis of antitumor activity of CD40L, RANKL, and 4-1BBL in vivo following intratumoral administration of viral vectors or transduced dendritic cellsTHE JOURNAL OF GENE MEDICINE, Issue 2 2006Zoya R. Yurkovetsky Abstract The tumor necrosis factor (TNF) family comprises a group of ligands that regulate cell proliferation, differentiation, activation, maturation and apoptosis through interaction with the corresponding TNF receptor family members. In this study, we have evaluated whether adenovirus-mediated intratumoral gene transfer of CD40L, RANKL, or 4-1BBL elicits an immune response to established murine MC38 and TS/A tumors. Intratumoral administration of the recombinant adenoviral vectors expressing CD40L, RANKL or 4-1BBL 7 days post-tumor cell inoculation resulted in significant inhibition of MC38 tumor growth for all three ligands when compared with control groups treated with either saline or control adenovirus. However, intratumoral injection of Ad-4-1BBL or Ad-CD40L resulted in a significantly stronger inhibition of TS/A tumor progression than did Ad-RANKL treatment. We also demonstrated that intratumoral administration of dendritic cells (DC) transduced with adenoviral vectors encoding the TNF-related ligands resulted in a significant inhibition of MC38 tumor growth as compared with control groups treated with Ad-LacZ-transduced DC or saline-treated DC. In addition, DC overexpressing CD40L secreted considerably more IL-12 and expressed higher levels of the co-stimulatory molecules, CD80, CD86 and CD40, than did DC overexpressing LacZ, 4-1BBL or RANKL. We have also demonstrated that DC/CD40L, DC/4-1BBL, and DC/RANKL survived significantly longer than control DC or DC infected with the LacZ vector. Taken together, these results demonstrate that adenoviral gene transfer of CD40L, RANKL or 4-1BBL elicit a significant antitumor effect in two different tumor models, with CD40L gene transfer inducing the strongest antitumor effect. Copyright © 2005 John Wiley & Sons, Ltd. [source] Simple route to ferrocenylalkyl nucleobases.APPLIED ORGANOMETALLIC CHEMISTRY, Issue 6 2009Antitumor activity in vivo Abstract Ferrocenylalkyl nucleobases (1,14) were prepared via the reaction of the ,-(hydroxy)alkyl ferrocenes FcCHR(OH) (Fc = ferrocenyl; R = H, Me, Et, Ph) with thymine, cytosine, iodo-cytosine and adenine in DMSO at 100 °C, yields being 50,80%. The antitumor activities of ferrocenylmethyl thymine (1) against solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were studied in vivo. Therapeutic synergism of antitumor activity against LLC was demonstrated in the case of combined application of compound 1 with anticancer drug cyclophosphamide. Copyright © 2009 John Wiley & Sons, Ltd. [source] Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft modelsCANCER SCIENCE, Issue 12 2004Fumiko Taguchi ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor (VEGF) receptor-2 (KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 has been shown to inhibit angiogenesis and tumor growth in a range of tumor models. Gefitinib ("Iressa") is an selective EGFR tyrosine kinase inhibitor (TKI) that blocks signal transduction pathways. We examined the antitumor activity of ZD6474 in the gefitinib-sensitive lung adenocarcinoma cell line, PC-9, and a gefitinib-resistant variant (PC-9/ZD). PC-9/ZD cells showed cross-resistance to ZD6474 in an in vitro dye formation assay. In addition, ZD6474 showed dose-dependent inhibition of EGFR phosphorylation in PC-9 cells, but inhibition was only partial in PC-9/ZD cells. ZD6474-mediated inhibition of tyrosine residue phosphorylation (Tyr992 and Tyr1045) on EGFR was greater in PC-9 cells than in PC-9/ZD cells. These findings suggest that the inhibition of EGFR phosphorylation by ZD6474 can contribute a significant, direct growth-inhibitory effect in tumor cell lines dependent on EGFR signaling for growth and/or survival. The effect of ZD6474 (12.5,50 mg/kg/day p.o. for 21 days) on the growth of PC-9 and PC-9/ZD tumor xenografts in athymic mice was also investigated. The greatest effect was seen in gefitinib-sensitive PC-9 tumors, where ZD6474 treatment (>12.5 mg/kg/day) resulted in tumor regression. Dose-dependent growth inhibition, but not tumor regression, was seen in ZD6474-treated PC-9/ZD tumors. These studies demonstrate that the additional EGFR TKI activity may contribute significantly to the anti-tumor efficacy of ZD6474, in particular in those tumors that are dependent on continued EGFR-signaling for proliferation or survival. In addition, these results provide a preclinical rationale for further investigation of ZD6474 as a potential treatment option for both EGFR-TKI-sensitive and EGFR-TKI-resistant tumors. [source] DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f: Potent antitumor activities in various murine tumor modelsCANCER SCIENCE, Issue 2 2004Eiji Kumazawa DE-310 is a novel macromolecular conjugate composed of DX-8951f, a camptothecin analog, and a carboxymethyldextran polyalcohol carrier, which are covalently linked via a peptidyl spacer. In a murine Meth A (fibrosarcoma) solid tumor model, once daily×5 treatments (qd×5) with DX-8951f at the maximum tolerated dose (MTD) were required to shrink the tumor, and DX-8951f (qd×5) at 1/4 MTD was required to inhibit tumor growth. A single treatment (qd×1) with DE-310 at the MTD or 1/4 MTD shrank the tumor, with no body weight loss occurring at 1/4 MTD. Even at 1/16 MTD, DE-310 inhibited tumor growth. In a long-term assay, Meth A solid tumors disappeared in mice treated with DE-310 (qd×1) at the MTD and 1/2 MTD, and all 6 mice remained tumor-free on the 60th day after administration. Repeated injection (4 times) on schedules of every 3 days, 7 days or 14 days demonstrated that multiple treatment with DE-310 produced greater tumor growth delay than a single treatment with DE-310. Against 5 human tumor (colon and lung cancer) xenografts in mice, DE-310 (qd×1) was as effective as DX-8951f administered once every 4 days, 4 times. The life-prolonging activity of DE-310 was assessed in lung (3LL, Lewis lung carcinoma) and liver (M5076, histiocytoma) metastasis models. Against 3LL, DE-310 (qdx1) at the MTD to 1/3 MTD significantly prolonged survival, with an increase in life span (ILS) of 4.8- to 1.6-fold, respectively, over that in untreated control mice. Also, DE-310 (qd×1) significantly prolonged survival in the liver metastasis model of M5076. These results demonstrate that DE-310 is a promising agent for the treatment of cancer. [source] | ||||||||||||||||||||||||||||