28 results on '"Kerbel, Robert S."'
Search Results
2. The multiple personality disorder phenotype(s) of circulating endothelial cells in cancer
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Bertolini, Francesco, Mancuso, Patrizia, Braidotti, Paola, Shaked, Yuval, and Kerbel, Robert S.
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- 2009
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3. A CD276 Antibody Guided Missile with One Warhead and Two Targets: The Tumor and Its Vasculature.
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Khan, Kabir A. and Kerbel, Robert S.
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CANCER cells , *BLOOD-vessel abnormalities , *VASCULAR endothelial growth factor genetics , *GLYCOPROTEIN hormones , *MOLECULAR structure of carrier proteins , *PHYSIOLOGY - Abstract
In this issue of Cancer Cell , Seaman et al. demonstrate that antibody drug conjugates (ADCs) against CD276 expressed by tumor cells and tumor vasculature have promising anti-tumor activity while showing little toxicity. Importantly, these agents have the potential to target both angiogenic vessels and non-angiogenic vessels co-opted by tumor cells. [ABSTRACT FROM AUTHOR]
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- 2017
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4. Controlling angiogenesis in breast cancer: A systematic review of anti-angiogenic trials.
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Mackey, John R., Kerbel, Robert S., Gelmon, Karen A., McLeod, Deanna M., Chia, Stephen K., Rayson, Daniel, Verma, Sunil, Collins, Loretta L., Paterson, Alexander H.G., Robidoux, André, and Pritchard, Kathleen I.
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Abstract: Purpose: Angiogenesis is critical for tumor growth and a promising therapeutic target. This review will summarize and analyze data from clinical trials of anti-angiogenic agents in the treatment of breast cancer (BC). Design: A systematic search of PubMed and conference databases was performed to identify reports of randomized clinical trials investigating specific anti-angiogenic agents in the treatment of BC. Results and discussion: Phase III trials in advanced BC have demonstrated a reduction in the risk of disease progression (22–52%), improved response rates and net improvements in progression-free survival of 1.2 to 5.5months, but no significant improvements in overall survival with the addition of bevacizumab to chemotherapy. Results of phase III trials in early breast cancer have been inconsistent. Bevacizumab-containing regimens have also been associated with higher overall adverse event rates compared to chemotherapy alone. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while randomized phase II trials of sorafenib and pazopanib have improved some outcomes when combined with chemotherapy or targeted therapy compared to controls. In addition to expected vascular class safety signals, tyrosine kinase inhibitors show “off-target” side effects. Ongoing clinical trials evaluating combinatorial strategies based on biological synergies and translational studies identifying biological predictors of response will be crucial to establish meaningful clinical benefits in selected BC populations. Conclusion: Most trials of anti-angiogenic agents in BC have reported improved response rate and progression-free survival but no increase in overall survival compared to chemotherapy alone. Optimizing the therapeutic indices of these agents is a focus of ongoing research and will be critical to their future development. [Copyright &y& Elsevier]
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- 2012
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5. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy.
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Munoz, Raquel, Shaked, Yuval, Bertolini, Francesco, Emmenegger, Urban, Man, Shan, and Kerbel, Robert S.
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CANCER chemotherapy ,BREAST cancer ,XENOGRAFTS ,METASTASIS ,BIOMARKERS ,TAMOXIFEN - Abstract
Summary: We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a variety of preclinical models, including human breast cancer xenografts. The advantages of metronomic–maintenance-type chemotherapy regimens include significantly reduced host toxicity, potentially reduced costs, increased convenience for patients when oral chemotherapy drugs are used, and the possibility of adopting chronic combination therapies involving conventional chemotherapy drugs and cytostatic molecularly targeted therapies. However, a disadvantage is the empiricism associated with determining the optimal biologic dose (OBD). Recently, we have developed a surrogate biomarker approach involving measurement of circulating endothelial progenitor cells (CEPs) in peripheral blood to help determine the OBD of anti-angiogenic drugs or treatments, including metronomic chemotherapy. Using this approach we determined the OBD for different metronomic chemotherapy regimens and then tested the effect of such drugs for the treatment of established, advanced (high volume) and widespread human breast cancer metastases in immunodeficient mice. This treatment strategy, which was maintained for over 6 months, with no breaks, resulted in marked prolongation of survival and was devoid of overt toxicity. These results suggest the possibility of using metronomic chemotherapy regimens as an adjuvant therapy for early-stage disease, including breast cancer, as was demonstrated recently using long-term daily low-dose UFT for the treatment of early-stage resected non-small cell lung cancer or UFT in combination for early stage breast cancer combined with tamoxifen. [Copyright &y& Elsevier]
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- 2005
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6. Acquired resistance to EGFR inhibitors: mechanisms and prevention strategies
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Viloria-Petit, Alicia M. and Kerbel, Robert S.
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EPIDERMAL growth factor , *CELL receptors , *DRUG resistance , *IMMUNOGLOBULINS - Abstract
Potent and specific, or relatively specific, inhibitors of epidermal growth factor receptor (EGFR) signaling, including monoclonal antibodies and small molecular weight compounds, have been successfully developed. Both types of agent have been found to have significant antitumor activity, especially when used in combination with radio- hormone- and chemotherapy in preclinical studies. Because of the potentiation of the conventional drug activity in these combination settings, inhibitors of EGFR signaling have often been referred to as sensitizers for chemotherapy or radiation, as well as drug resistance reversal agents. Phase II clinical trials in head-and-neck as well as lung cancer suggested this concept of chemosensitization might translate into the clinic, but this remains to be definitively proven in randomized, double-blind Phase III trials. Given the extensive preclinical literature on EGFR blocking drugs and the advanced clinical development of such agents, it is surprising that the possibility of development of acquired resistance to the EGFR inhibitors themselves, a common clinical problem with virtually all other currently used anticancer drugs, remains a largely unexplored subject of investigation. Here we summarize some of the possible mechanisms that can result in acquired resistance to EGFR-targeting drugs. Alternative combination therapies to circumvent and delay this problem are suggested. [Copyright &y& Elsevier]
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- 2004
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7. Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed
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Kerbel, Robert S.
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GROWTH factors , *CYTOKINES , *TUMORS , *CANCER cells , *ONCOLOGY , *ADENOMA - Abstract
Summary: There is a large family of known proangiogenic growth factors, many of which can be expressed by a single tumor, especially in advanced stages of disease. Such redundancy, which can be amplified by hypoxia, has long been suspected as a potential cause of acquired resistance when tumors are treated with highly specific targeted antiangiogenic drugs. Definitive preclinical evidence for antiangiogenic drug evasion by alternate pathways of angiogenesis in tumor cells, likely induced by antiangiogenic drug-mediated increases in tumor hypoxia, is reported in this issue of Cancer Cell (); it has major implications for the development of strategies to prolong the effectiveness of antiangiogenic drugs as monotherapies, and for their use as chemosensitizing agents in combination treatment strategies. [Copyright &y& Elsevier]
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- 2005
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8. Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early or late stage breast cancer metastatis.
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Kerbel, Robert S., Guerin, Eric, Francia, Giulio, Xu, Ping, Lee, Christina R., Ebos, John M.L., and Man, Shan
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DRUG efficacy ,BREAST cancer ,LABORATORY mice ,NEOVASCULARIZATION ,XENOGRAFTS ,ADJUVANT treatment of cancer ,ANIMAL models of cancer ,ANTINEOPLASTIC agents - Abstract
Abstract: Historically, preclinical tumor therapy models in mice have frequently been deficient in predicting subsequent clinical activity; over-prediction of clinical anti-tumor efficacy is common. Several approaches are being made in an attempt to improve the clinical relevance of preclinical models, and include the use of genetically engineered mouse models (GEMMs) of cancer or patient derived xenografts (PDXs). Here we summarize, in the context of breast cancer, another approach, namely, the development of postsurgical models of either macroscopic or microscopic metastatic disease to mimic metastatic or adjuvant therapy. To do so we used in vivo selected metastatic variants of established human breast cancer cell lines such as MDA-MB-231. Testing antiangiogenic drugs such as the oral tyrosine kinase inhibitor (TKI) sunitinib alone or combined with chemotherapy in models involving treatment of established primary tumors invariably resulted in demonstrable anti-tumor activity. In contrast, identical treatments of postsurgical mice with advanced metastatic disease did not: survival times were not prolonged. This reflects multiple failed phase III trials of sunitinib based therapies in metastatic breast cancer patients. However, using a VEGF pathway targeting antibody drug instead of a TKI, with (paclitaxel) chemotherapy, resulted in anti-tumor activity in the metastatic setting, partially reflecting prior clinical results of the E2100 phase III trial of weekly paclitaxel plus bevacizumab. Other experiments involving postsurgical adjuvant treatment of early stage disease foreshadowed the phase III clinical trial failures of adjuvant bevacizumab in colorectal or breast cancer. In contrast, some investigational metronomic oral chemotherapy protocols alone or in combination with an antiangiogenic drug demonstrated potent activity in the advanced metastatic setting; these encouraging results have yet to be validated in randomized phase III clinical trials, which are underway based on some encouraging phase II clinical trial results. We have also observed circumstances where mice with advanced systemic disease, when successfully treated so as to prolong survival, sometimes relapse with brain metastases, reflecting a similar clinical phenomenon. Given our overall findings, we suggest that using preclinical mouse tumor models which mimic postsurgical adjuvant or metastatic therapy may be a promising strategy to help improve the ability to predict subsequent clinical outcomes. [Copyright &y& Elsevier]
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- 2013
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9. Reappraising antiangiogenic therapy for breast cancer.
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Kerbel, Robert S.
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BREAST cancer chemotherapy ,CLINICAL trials ,BEVACIZUMAB ,METASTASIS ,DISEASE progression ,BIOMARKERS - Abstract
Summary: Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed. [Copyright &y& Elsevier]
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- 2011
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10. Issues regarding improving the impact of antiangiogenic drugs for the treatment of breast cancer.
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Kerbel, Robert S.
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BREAST cancer treatment ,BEVACIZUMAB ,MONOCLONAL antibodies ,DRUG resistance in cancer cells ,TRANSFORMING growth factors ,CANCER invasiveness ,VASCULAR endothelial growth factors - Abstract
Summary: One of the major recent clinical advances in cancer treatment is the use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib. Bevacizumab, the monoclonal anti-VEGF antibody, has been approved for the first line treatment of metastatic breast cancer (MBC) when combined with taxane. However, the clinical benefits are modest; despite a doubling of response rates and significant prolongation of progression free survival times, no increase in overall survival is attained. This review summarizes some of the possibilities to account for this discrepant result. These include rapid development of acquired drug resistance due to the redundancy of proangiogenic growth factors, acceleration of tumor growth after antiangiogenic drug treatments are stopped, and increases in tumor cell malignant aggressiveness driven by mechanisms such as increased tumor hypoxia. Some possible strategies to improve the benefits of antiangiogenic drug therapy are discussed such as prolonging the treatment beyond tumor progression, combination with other therapeutic modalities, e.g. long term (‘maintenance’) low-dose metronomic chemotherapy or additional targeted/biologic drugs, e.g. trastuzumab. [Copyright &y& Elsevier]
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- 2009
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11. High-frequency 3-D color-flow imaging of the microcirculation
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Goertz, David E., Yu, Joanne L., Kerbel, Robert S., Burns, Peter N., and Foster, F.Stuart
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BLOOD flow , *NONINVASIVE diagnostic tests - Abstract
High-frequency (> 20 MHz) ultrasound (US) flow imaging has the potential to be an important tool for assessing microvascular blood flow in superficial tissues noninvasively. In this paper, we describe the development and evaluation of a 3-D US flow imaging system capable of operating at center frequencies in the 20- to 50-MHz range. Flow images are made for tissue volumes of sizes up to 10 mm laterally and 5 mm in depth, permitting a range of scientific and clinical applications. To acquire data sets in a reasonable time, the 2-D sections were derived from data collected with a transducer that was scanning continuously in a direction perpendicular to the beam axis. Due to spectral broadening effects induced by scanning tissue, significant tradeoffs must be made between frame rate, lateral resolution and the minimum detectable blood velocity. 3-D flow images were reconstructed with flow data acquired from a series of adjacent planes. The system was evaluated at a center frequency of 50 MHz, using two PVDF transducers with lateral resolutions of 43 μm and 65 μm and axial resolutions of 66 μm to 72 μm, respectively. Velocity ranges were from below 1 mm/s to 25 mm/s. In vivo validation experiments using the mouse ear demonstrated the ability to follow branching patterns of closely spaced microvessels from 30 μm to 100 μm in diameter. Experiments conducted on mouse tumors successfully imaged microvessel morphology in the tumor microcirculation. (E-mail: goetzda@sten.sunnybrook.utoronto.ca) [Copyright &y& Elsevier]
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- 2003
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12. Tumor-Associated Fibroblasts as “Trojan Horse” Mediators of Resistance to Anti-VEGF Therapy
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Francia, Giulio, Emmenegger, Urban, and Kerbel, Robert S.
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FIBROBLASTS , *CELL tumors , *VASCULAR endothelial growth factors , *DRUG resistance , *CANCER cells , *TARGETED drug delivery - Abstract
While targeting VEGF has shown success against a number of human cancers, drug resistance has resulted in compromised clinical benefits. In this issue of Cancer Cell, report that tumors resistant to anti-VEGF therapy stimulate tumor-associated fibroblasts to express proangiogenic PDGF-C, implicating it as a potential therapeutic target. [Copyright &y& Elsevier]
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- 2009
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13. miR-30b/30d Regulation of GalNAc Transferases Enhances Invasion and Immunosuppression during Metastasis
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Gaziel-Sovran, Avital, Segura, Miguel F., Di Micco, Raffaella, Collins, Mary K., Hanniford, Douglas, Vega-Saenz de Miera, Eleazar, Rakus, John F., Dankert, John F., Shang, Shulian, Kerbel, Robert S., Bhardwaj, Nina, Shao, Yongzhao, Darvishian, Farbod, Zavadil, Jiri, Erlebacher, Adrian, Mahal, Lara K., Osman, Iman, and Hernando, Eva
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CANCER cells , *TRANSFERASES , *IMMUNOSUPPRESSION , *METASTASIS , *GENE expression , *CYTOKINES , *GENETIC regulation , *CANCER invasiveness - Abstract
Summary: To metastasize, a tumor cell must acquire abilities such as the capacity to colonize new tissue and evade immune surveillance. Recent evidence suggests that microRNAs can promote the evolution of malignant behaviors by regulating multiple targets. We performed a microRNA analysis of human melanoma, a highly invasive cancer, and found that miR-30b/30d upregulation correlates with stage, metastatic potential, shorter time to recurrence, and reduced overall survival. Ectopic expression of miR-30b/30d promoted the metastatic behavior of melanoma cells by directly targeting the GalNAc transferase GALNT7, resulted in increased synthesis of the immunosuppressive cytokine IL-10, and reduced immune cell activation and recruitment. These data support a key role of miR-30b/30d and GalNAc transferases in metastasis, by simultaneously promoting cellular invasion and immunosuppression. [Copyright &y& Elsevier]
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- 2011
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14. Metronomic S-1 Chemotherapy and Vandetanib: An Efficacious and Nontoxic Treatment for Hepatocellular Carcinoma.
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Iwamoto, Hideki, Torimura, Takuji, Nakamura, Toru, Hashimoto, Osamu, Inoue, Kinya, Kurogi, Junichi, Niizeki, Takashi, Kuwahara, Reiichiro, Abe, Mitsuhiko, Koga, Hiromori, Yano, Hirohisa, Kerbel, Robert S., Ueno, Takato, and Sata, Michio
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LIVER cancer , *FLUOROURACIL , *APOPTOSIS , *IMMUNOHISTOCHEMISTRY , *THROMBOSPONDINS - Abstract
BACKGROUND: Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at non-toxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC). METHODS: We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot. RESULTS: Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib. CONCLUSION: Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC. [ABSTRACT FROM AUTHOR]
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- 2011
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15. Tumors That Acquire Resistance to Low-Dose Metronomic Cyclophosphamide Retain Sensitivity to Maximum Tolerated Dose Cyclophosphamide.
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Emmenegger, Urban, Francia, Giulio, Chow, Annabelle, Shaked, Yuval, Kouri, Andrew, Man, Shan, and Kerbel, Robert S.
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DRUG resistance in cancer cells , *CYCLOPHOSPHAMIDE , *PROSTATE cancer treatment , *DRUG dosage , *DRUG therapy , *LABORATORY mice - Abstract
Low-dose metronomic (LDM) chemotherapy is emerging as an alternative or supplemental dosing strategy to conventional maximum tolerated dose (MTD) chemotherapy. It is characterized primarily, but not exclusively, by anti-angiogenic mechanisms of action and the absence of high-grade adverse effects commonly seen with MTD chemotherapy. However, similar to other anticancer therapies, inherent resistance to LDM chemotherapy is common. Moreover, even tumors that initially respond to metronomic regimens eventually develop resistance through mechanisms that are as yet unknown. Thus, we have developed in vivo models of PC-3 human prostate cancer cells resistant to extended LDM cyclophosphamide therapy. Such PC-3 variants show stable resistance to LDM cyclophosphamide in vivo yet retain in vitro sensitivity to 4-hydroperoxy-cyclophosphamide (precursor of the active cyclophosphamide metabolite 4-hydroxy-cyclophosphamide) and other chemotherapeutic agents, namely, docetaxel and doxorubicin. Moreover, LDM cyclophosphamide-resistant PC-3 variants remain sensitive to MTD cyclophosphamide therapy in vivo. Conversely, PC-3 variants made resistant in vivo to MTD cyclophosphamide show varying levels of resistance to metronomic cyclophosphamide when grown in mice. These results and additional studies of variants of the breast cancer cell line MDA-MB-231 suggest that resistance to LDM cyclophosphamide is a distinct phenomenon from resistance to MTD cyclophosphamide and that LDM cyclophosphamide administration does not select for MTD chemotherapy resistance. As such, our findings have various implications for the clinical use of metronomic chemotherapy. [ABSTRACT FROM AUTHOR]
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- 2011
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16. Development of a Resistance-like Phenotype to Sorafenib by Human Hepatocellular Carcinoma Cells Is Reversible and Can Be Delayed by Metronomic UFT Chemotherapy.
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Tang, Terence C., Shan Man, Ping Xu, Francia, Giulio, Hashimoto, Kae, Emmenegger, Urban, and Kerbel, Robert S.
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DRUG resistance , *LIVER cancer , *DRUG therapy , *XENOGRAFTS , *PHENOTYPES - Abstract
Acquired resistance to antiangiogenic drugs, such as sorafenib, is amajor clinical problem. We studied development of a resistance to sorafenib in new preclinical models of human hepatocellular carcinoma (HCC) along with a strategy to delay such resistance--combination with metronomic chemotherapy. Three different xenograft models were studied using human Hep3B HCC cells, which are highly responsive to sorafenib, namely, orthotopic and subcutaneous transplant in severe combined immunodeficientmice, and an orthotopic transplant in nudemice. The complementary DNA for the β-subunit of human choriogonadotropin was transfected into HCC cells, and urine levels of the protein were monitored as a surrogate of tumor burden. Extended daily treatments, sometimes interrupted by a break period of 3 to 7 days to allow recovery from toxicity at sorafenib doses of 30 to 60 mg/kg, were maintained until and after evidence of tumor relapse. Initially responsive tumors seemed to develop a resistance-like phenotype after long-term daily treatment (e.g., >42 days) at doses of 30 to 60 mg/kg. Transplantation of cell lines established from progressing tumors into new hosts showed that the resistant phenotype was not propagated. Furthermore, a regimen of daily metronomic uracil + tegafur (UFT, an oral 5-fluorouracil prodrug) chemotherapy with a less toxic regimen of sorafenib (15 mg/kg per day) significantly delayed the onset of resistance (>91 days). In conclusion, development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafenib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such resistance. [ABSTRACT FROM AUTHOR]
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- 2010
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17. Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma.
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Tang, Terence C., Shan Man, Lee, Christina R., Ping Xu, and Kerbel, Robert S.
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LIVER cancer , *DRUG therapy , *FLUOROPYRIMIDINES , *TUMORS , *CELL lines , *ANTHRACYCLINES , *GROWTH factors - Abstract
Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficientmice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfectedwith the gene encoding secretable β-subunit human choriogonadotropin (β-hCG),whichwas used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti--vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicitywas observed using either single or doubletmetronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survivalwas observed using various combinations ofmetronomic chemotherapy regimens such as UFT+CTXwithDC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment. [ABSTRACT FROM AUTHOR]
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- 2010
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18. Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis
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Ebos, John M.L., Lee, Christina R., Cruz-Munoz, William, Bjarnason, Georg A., Christensen, James G., and Kerbel, Robert S.
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NEOVASCULARIZATION inhibitors , *METASTASIS , *TUMOR growth , *LABORATORY mice , *PROTEIN-tyrosine kinase inhibitors , *ANIMAL models of cancer - Abstract
Summary: Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments. [Copyright &y& Elsevier]
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- 2009
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19. Rapid Chemotherapy-Induced Acute Endothelial Progenitor Cell Mobilization: Implications for Antiangiogenic Drugs as Chemosensitizing Agents
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Shaked, Yuval, Henke, Erik, Roodhart, Jeanine M.L., Mancuso, Patrizia, Langenberg, Marlies H.G., Colleoni, Marco, Daenen, Laura G., Man, Shan, Xu, Ping, Emmenegger, Urban, Tang, Terence, Zhu, Zhenping, Witte, Larry, Strieter, Robert M., Bertolini, Francesco, Voest, Emile E., Benezra, Robert, and Kerbel, Robert S.
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CANCER chemotherapy , *ANTINEOPLASTIC agents , *TUMORS , *PACLITAXEL , *CANCER treatment , *IMMUNOGLOBULINS - Abstract
Summary: Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine. [Copyright &y& Elsevier]
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- 2008
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20. Phosphorylated Epidermal Growth Factor Receptor on Tumor-Associated Endothelial Cells Is a Primary Target for Therapy with Tyrosine Kinase Inhibitors.
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Kuwai, Toshio, Nakamura, Toru, Sasaki, Takamitsu, Sun-Jin Kim, Fan, Dominic, Villares, Gabriel J., Zigler, Maya, Hua Wang, Bar-Eli, Menashe, Kerbel, Robert S., and Fidler, Isaiah J.
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EPIDERMAL growth factor , *ENDOTHELIUM , *TUMORS , *PROTEIN-tyrosine kinase inhibitors , *COLON cancer , *LENTIVIRUSES , *RNA , *CELL lines - Abstract
We determined whether phosphorylated epidermal growth factor receptor (EGFR) expressed on tumor-associated endothelial cells is a primary target for therapy with EGFR tyrosine kinase inhibitors (TKIs). Human colon cancer cells SW620CE2 (parental) that do not express EGFR or human epidermal growth factor receptor 2 (HER2) but express transforming growth factor α (TGF-α) were transduced with a lentivirus carrying nontargeting small hairpin RNA (shRNA) or TGF-α shRNA. The cell lines were implanted into the cecum of nude mice. Two weeks later, treatment began with saline, 4-[R]-phenethylamino-6-[hydroxyl] phenyl-7H-pyrrolo [2,3-D] -pyrimidine (PKI166), or irinotecan. Endothelial cells in parental and nontargeting shRNA tumors expressed phosphorylated EGFR. Therapy with PKI166 alone or with irinotecan produced apoptosis of these endothelial cells and necrosis of the EGFR-negative tumors. Endothelial cells in tumors that did not express TGF-α did not express EGFR, and these tumors were resistant to treatment with PKI166. The response of neoplasms to EGFR antagonists has been correlated with EGFR mutations, HER2 expression, Akt activation, and EGFR gene copy number. Our present data using colon cancer cells that do not express EGFR or HER2 suggest that the expression of TGF-α by tumor cells leading to the activation of EGFR in tumor-associated endothelial cells is a major determinant for the susceptibility of neoplasms to therapy by specific EGFR-TKI. [ABSTRACT FROM AUTHOR]
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- 2008
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21. Molecular and cellular biomarkers for angiogenesis in clinical oncology
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Bertolini, Francesco, Mancuso, Patrizia, Shaked, Yuval, and Kerbel, Robert S.
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ONCOLOGY , *NEOVASCULARIZATION , *DRUG dosage , *ENDOTHELIUM , *BIOMARKERS - Abstract
Medical oncologists are increasingly using anti-angiogenic drugs, but identifying the best-suited drug and the optimal dosage and schedule for treatment of patients remain challenging issues. Circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs) are modulated in a variety of diseases including cancer, and are promising surrogate biomarkers in oncology. Molecular surrogate markers, on the other hand, are more scanty at the present time, because the identification of truly endothelial cell-restricted genes and/or antigens is complex. Here, we discuss the biological and technical facets of the search and validation of new biomarkers for angiogenesis. [Copyright &y& Elsevier]
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- 2007
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22. Detecting Vascular Changes in Tumour Xenografts Using Micro-Ultrasound and Micro-CT Following Treatment with VEGFR-2 Blocking Antibodies
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Cheung, Alison M.Y., Brown, Allison S., Cucevic, Viviene, Roy, Marcia, Needles, Andrew, Yang, Victor, Hicklin, Daniel J., Kerbel, Robert S., and Foster, F. Stuart
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MEDICAL imaging systems , *XENOGRAFTS , *TRANSPLANTATION of organs, tissues, etc. , *VASCULAR endothelial growth factors , *ANTINEOPLASTIC agents , *MELANOMA treatment , *THERAPEUTIC use of monoclonal antibodies , *NEOVASCULARIZATION inhibitors , *ANIMAL experimentation , *CELL receptors , *COMPARATIVE studies , *COMPUTED tomography , *RESEARCH methodology , *MEDICAL cooperation , *MELANOMA , *MICE , *RESEARCH , *EVALUATION research , *TREATMENT effectiveness , *CANCER cell culture , *PATHOLOGIC neovascularization , *THERAPEUTICS - Abstract
Abstract: Blockade of vascular endothelial growth factor (VEGF) binding to its receptors on endothelial cells has been shown preclinically to induce tumour growth inhibition. Using ultrasound biomicroscopy (UBM) or micro-ultrasound imaging and micro-computed tomography (micro-CT) analysis, we have examined the effects of DC101, a highly specific vascular endothelial growth factor receptor-2 (VEGFR-2)-targeting antibody, in inducing growth inhibition and functional vascular changes in established melanoma (MeWo) xenografts in mice. Postprocessing of UBM imaging loops for speckle variance was introduced to estimate the level of functional blood flow in tumours. Perfused tumour area visualized by speckle variance revealed decreased blood flow within 48 h after DC101 injection (control versus DC101: 1.90 ± 0.25% versus 1.01 ± 0.11%, p < 0.01) and following a 3-wk DC101 therapy (control versus DC101: 0.76 ± 0.14% versus 0.45 ± 0.05%, p = 0.04), suggesting that VEGFR-2 blockade mediates both early and long-term effects on tumour blood flow. The growth of xenografts was significantly inhibited after treating with DC101 for 3 wk compared with controls. In addition to UBM, we examined the tumour vasculature in three-dimension (3D) using contrast-enhanced Micro-CT imaging, which displayed a reduction in the number of tumour vessels following extended VEGFR-2 blockade (vascular density of control versus DC101: 48.4 ± 5.4% versus 20.6 ± 1.8%). Lastly, decreased microvessel density (MVD) was noted in DC101-treated xenografts (3 wk) by performing immunohistochemical staining of endothelial marker CD34. Our study investigates tumour response to DC101 using complementing micro-ultrasound and micro-CT imaging tools. (stuart@swri.ca) [Copyright &y& Elsevier]
- Published
- 2007
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23. Ras Oncogene Triggers Up-regulation of cIAP2 and XIAP in Intestinal Epithelial Cells EPIDERMAL GROWTH FACTOR RECEPTOR-DEPENDENT AND -INDEPENDENT MECHANISMS OF ras-INDUCED TRANSFORMATION.
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Zaiping Liu, Hongbing Li, Derouet, Mathieu, Filmus, Jorge, LaCasse, Eric C., Korneluk, Robert G., Kerbel, Robert S., and Rosen, Kirill V.
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RENIN-angiotensin system , *ALDOSTERONE , *EXTRACELLULAR matrix , *CONNECTIVE tissues , *APOPTOSIS , *EPITHELIAL cells , *EPITHELIUM , *BIOCHEMISTRY - Abstract
Detachment of normal epithelial cells from the extracellular matrix (ECM) triggers apoptosis, a phenomenon called anoikis. Conversely, carcinomas (cancers of epithelial origin) represent three-dimensional disorganized multicellular masses in which cells are deprived of adhesion to the ECM but remain viable. Resistance of cancer cells to anoikis is thought to be critical for tumor progression. However, the knowledge about molecular mechanisms of this type of resistance remains limited. Herein we report that ras oncogene, an established inhibitor of anoikis, triggers a significant upregulation of anti-apoptotic proteins cIAP2 and XIAP in intestinal epithelial cells. We also observed that the effect of ras on cIAP2 requires ras-induced autocrine production of transforming growth factor a (TGF-α), a ligand for epidermal growth factor receptor, whereas ras-triggered up-regulation of XIAP is TGF-α-independent. Moreover, overexpression of either cIAP2 or XIAP in nonmalignant intestinal epithelial cell was found to block anoikis. In addition, an established IAP antagonist Smac or Smac-derived cell-permeable peptide suppressed ras-induced anoikis resistance and subsequent anchorage-independent growth of ras-transformed cells. We conclude that ras-induced overexpression of cIAP2 and XIAP significantly contributes to the ability of ras-transformed intestinal epithelial ceils to survive in the absence of adhesion to the ECM and grow in a three-dimensional manner. [ABSTRACT FROM AUTHOR]
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- 2005
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24. Careful Decoy Receptor Titering is Required to Inhibit Tumor Angiogenesis While Avoiding Adversely Altering VEGF Bioavailability
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Davidoff, Andrew M., Ng, Catherine Y.C., Zhang, Youbin, Streck, Christian J., Mabry, Stephanie J., Barton, Susan H., Baudino, Troy, Zhou, Junfang, Kerbel, Robert S., Vanin, Elio F., and Nathwani, Amit C.
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NEOVASCULARIZATION , *THERAPEUTICS , *TUMORS , *NEUROBLASTOMA - Abstract
Abstract: To inhibit tumor-induced angiogenesis, the VEGF signaling pathway was targeted using AAV vectors encoding a VEGF decoy receptor, a truncated, soluble form of the murine VEGF receptor-2 (tsFlk-1). This approach initially had significant anti-neuroblastoma efficacy in murine xenograft models of local and metastatic disease, but when higher circulating levels of tsFlk-1 were established, tumor growth was more aggressive than even in control mice. Part of the mechanism for this apparent tumor resistance was increased human VEGF expression by the tumor cells. However, further investigation revealed that although a greater amount of VEGF could be bound by higher levels of tsFlk-1, more VEGF also existed in an unbound state and was, therefore, available to support angiogenesis. This novel, tumor-independent mechanism for resistance to antiangiogenic strategies suggests that careful titering of angiogenesis inhibitors may be required to achieve maximal antitumor efficacy and avoid therapy resistance mediated, in part, by ligand bioavailability. This has important implications for therapeutic strategies that use decoy receptors and other agents, such as antibodies, to bind angiogenic factors, in an attempt to inhibit tumor neovascularization. [Copyright &y& Elsevier]
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- 2005
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25. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of antiangiogenesis
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Shaked, Yuval, Bertolini, Francesco, Man, Shan, Rogers, Michael S., Cervi, Dave, Foutz, Thomas, Rawn, Kimberley, Voskas, Daniel, Dumont, Daniel J., Ben-David, Yaacov, Lawler, Jack, Henkin, Jack, Huber, Jim, Hicklin, Daniel J., D'Amato, Robert J., and Kerbel, Robert S.
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NEOVASCULARIZATION , *NEOVASCULARIZATION inhibitors , *TUMORS , *ONCOLOGY , *CANCER - Abstract
Development of antiangiogenic therapies would be significantly facilitated by quantitative surrogate pharmacodynamic markers. Circulating peripheral blood endothelial cells (CECs) and/or their putative progenitor subset (CEPs) have been proposed but not yet fully validated for this purpose. Herein, we provide such validation by showing a striking correlation between highly genetically heterogeneous bFGF- or VEGF-induced angiogenesis and intrinsic CEC or CEP levels measured by flow cytometry, among eight different inbred mouse strains. Moreover, studies using genetically altered mice showed that levels of these cells are affected by regulators of angiogenesis, including VEGF, Tie-2, and thrombospondin-1. Finally, treatment with a targeted VEGFR-2 antibody caused a dose-dependent reduction in viable CEPs that precisely paralleled its previously and empirically determined antitumor activity. [Copyright &y& Elsevier]
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- 2005
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26. Selective anti-endothelial effects of protracted low-dose BAL-9504, a novel geranylgeranyl-transferase inhibitor
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Bocci, Guido, Danesi, Romano, Del Tacca, Mario, and Kerbel, Robert S.
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INTERFERONS , *DRUG therapy , *DRUGS - Abstract
Because the anti-endothelial effects of agents such as interferon alpha, endostatin, and various chemotherapeutic drugs appear to be optimal after protracted, frequent dosing, both in vitro and in vivo, using low concentrations/doses of drugs, we tested the geranylgeranyl transferase inhibitor BAL-9504 ((E,E,E) [2-oxo-2-[[(3,7,11,15-tetramethyl-2,6,10,14 hexadecatetraenyl)-oxy]amino]ethyl] phosphonic acid) in this manner on different human cell types, including endothelial, breast cancer cells and fibroblasts. We found that human endothelial cells were preferentially affected with respect to inhibition of proliferation, induction of apoptosis, suppression of adhesion to fibronectin, and blockade of cell migration, by daily exposure to low concentrations of BAL-9504 for 6 days. These results may have implications in terms of both increasing anti-tumor efficacy, mediated by antiangiogenic mechanisms, and reducing toxic side effects. [Copyright &y& Elsevier]
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- 2003
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27. Dok-R Binds c-Abl and Regulates Abl Kinase Activity and Mediates Cytoskeletal Reorganization.
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Master, Zubin, Tran, Jennifer, Bishnoi, Aseem, Chen, Stephen H., Ebos, John M., Van Slyke, Paul, Kerbel, Robert S., and Dumont, Daniel J.
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PROTEIN-tyrosine kinases , *PROTEIN-tyrosine phosphatase , *PHOSPHORYLATION - Abstract
Dok-R, also known as Dok-2/FRIP, belongs to the DOK family of signaling molecules that become tyrosinephosphorylated by several different receptor and cytoplasmic tyrosine kinases. Tyrosine phosphorylation of DOK proteins establishes high affinity binding sites for other signaling molecules leading to activation of a signaling cascade. Here we show that Dok-R associates with c-Abl directly via a constitutive SH3-mediated interaction and that this binding requires a PMMP motif in the proline-rich tail of Dok-R. The Dok-R-Abl interaction is further enhanced by an active c-Abl kinase, which requires the presence of its SH2 domain. Interaction of Dok-R with c-Abl also results in an increase in c-Abl tyrosine phosphorylation and kinase activity. Furthermore, we demonstrate that this increase in kinase activity correlates with a concomitant increase in c-Ablmediated biological activity as measured by the formation of aetin microspikes. Our data are the first to demonstrate that Dok-R and c-Abl interact in both a constitutive and inducible fashion and that Dok-R influences the intracellular kinase and biological activity of c-Abl. [ABSTRACT FROM AUTHOR]
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- 2003
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28. Collateral Expression of Proangiogenic and Tumorigenic Properties in Intestinal Epithelial Cell Variants Selected for Resistance to Anoikis.
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Rak, Janusz, Mitsuhashi, Yoshihiro, Sheehan, Cap, Krestow, Julia K, Florenes, Vivi Ann, Filmus, Jorge, and Kerbel, Robert S
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CELL death ,TUMOR genetics - Abstract
Although in vitro anchorage-independent growth is widely used as a marker of cell transformation, the biological implications of this trait are poorly understood. We previously demonstrated that enforced anchorage-independent growth of a nontumorigenic, immortalized epithelial cell line (IEC-18) in multicellular spheroid culture results in massive apoptotic cell death. This death process, termed anoikis, is prevented by expression of transforming oncogenes, which also confer tumorigenic competence. This study examines whether acquisition of an anoikis-resistant phenotype is causally related to the tumorigenic capacity of transformed epithelial cells. Parental IEC-18 cells were subjected to 10 cycles of selection for survival in speroid culture. Unlike parental cells, the resulting anoikis-resistant variants (AR1.10 and AR2.10) formed relatively large tumors in nude mice. Both anoikis-resistant sublines displayed upregulated expression of vascular endothelial growth factor (VEGF), a potent angiogenesis stimulator. VEGF121 overexpression alone did not induce tumorigenic conversion of parental IEC-18 cells, which remained highly susceptible to anoikis. We postulate that both anoikis-resistance and angiogenic-competence contribute to tumor formation. Development of anoikis-resistance can be then viewed as a precondition for expression of the tumorigenic phenotype. Our results suggest that even when angiogenesis is not a rate limiting factor (e.g. in vitro) the selective pressures of solid tumor–like, 3-dimensional growth conditions favoring anoikis resistance result in collateral induction of a proangiogenic phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 1999
- Full Text
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