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Experimental Therapeutics |
Molecular and Cell Biology Research, Sunnybrook and Women’s College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M4N 3M5 Canada [G. B., R. S. K.]; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037 [K. C. N.]; and Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093 [K. C. N.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Some preliminary evidence for such a preferential sensitivity of endothelial cells has been suggested on the basis of certain in vitro experiments. Thus, several groups have reported that very low (e.g., nanomolar) concentrations of certain drugs such as PTX (7 , 9) , topotecan, campthothecin (10) , or vinblastine (5 , 7 , 11) can significantly block endothelial cell growth, but not necessarily tumor cell growth in vitro. In addition, Vacca et al. (11) found that nanomolar or even picomolar concentrations of vinblastine, which did not cause significant antiproliferative effects against endothelial cells, could nevertheless suppress angiogenesis and certain endothelial cell functions considered relevant to angiogenesis, such as migration and protease production. Differential antiproliferative effects of chemotherapeutic drugs on vascular endothelial cells versus tumor cells have been noted with vinblastine, PTX, cisplatinum, and adriamycin (7) .
All of the aforementioned in vitro experiments usually involved a single drug exposure of between 24 and 72 h. However, this does not mirror the in vivo situation when protracted low-dose metronomic chemotherapy protocols are administered frequently (e.g., weekly; Ref. 4
) every 3 days (5)
, or even daily (8
, 12) . We, therefore, asked whether protracted exposures in vitro to certain chemotherapeutic drugs might reveal new and important aspects of the antiendothelial cell effects of low-dose metronomic chemotherapy regimens. The purpose of this study was to examine this question and, more specifically, to determine whether there is an "antiangiogenic window" for antineoplastic chemotherapeutic drugs in which drug activity, at comparatively low concentrations, is largely or specifically restricted to endothelial cells. To do so, we designed long-term in vitro assays in which human tumor cells, dermal fibroblasts, and macrovascular or microvascular endothelial cells were exposed daily, for up to 6 days, to various low concentrations of different, well known and novel chemotherapeutic drugs (Fig. 1)
, including 4-HC, PTX, an oral active taxane called BMS-275183 (13)
, DXR, EpoB (14)
, and the analogue 5-MP-EpoB (15)
. Our results show that vascular endothelial cells are, indeed, preferentially affected for properties such as proliferation and induction of apoptosis, by low concentrations of most of these drugs when exposed continuously for protracted periods of time (e.g., 6 days), but not for shorter periods of time (e.g., 24 h).
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cells and Culture Conditions.
HUVEC, HMVEC-d, and NHDFs were purchased from Clonetics. The human breast cancer cell line MDA-MB-435 was obtained from Dr. J. Lemontt (Genzyme Corp., Cambridge, MA); and its P-glycoprotein-positive multidrug-resistant variant of MDA-MB-435, called T0.1, was obtained from Dr. D. Cohen (Novartis) and was derived by in vitro exposure to increasing concentrations of PTX.
The HUVEC and HMVEC-d cells were maintained in MCDB131 culture medium (JRH Biosciences) supplemented with 10% heat-inactivated FBS (Life Technologies, Inc.), L-glutamine (2 mM; Life Technologies, Inc.), heparin (10 units/ml; Wyeth-Ayerst), epidermal growth factor (10 ng/ml; Upstate Biotechnology Inc.), and basic fibroblast growth factor (5 ng/ml; R&D Systems, Inc.). Human endothelial cells were routinely grown in 1% gelatin-coated tissue culture flasks (Nunc A/S). NHDFs were cultured in 5% FBS RPMI medium (Life Technologies, Inc.) supplemented with L-glutamine; the breast cancer cell lines were maintained and expanded as monolayer culture in 10% FBS DMEM (Life Technologies, Inc.) supplemented with L-glutamine; the T0.1-resistant variant was grown with the addition of 0.1 µM PTX. Cells were kept in a humidified atmosphere of 5% CO2 at 37°C and harvested with a solution of 0.25% trypsin-0.03% EDTA (Life Technologies, Inc.) when they were in log phase of growth, and maintained at the above-described culture conditions.
Cell Proliferation Assay.
In vitro chemosensitivity testing was performed on single-cell suspensions of HUVEC, HMVEC-d, NHDF, MDA-MB-435, and T0.1 cells plated in 96-well plastic plates (1% gelatin coated for the endothelial cells) and allowed to attach overnight. Each drug concentration was represented by at least 10 wells and replicated three times. Cells were treated for 24 h (3 x 103 cells/well in 200 µl of medium) or 144 h (1 x 103 and 0.5 x 103 cells/well of normal and cancer cells, respectively, in 200 µl of medium) with PTX (1–1,000 pM), BMS-275183 (1–1,000 pM), EpoB (1–1,000 pM), 5-MP-EpoB (1–1,000 pM), 4-HC (0.1–10,000 nM), and DXR (1–1,000 nM) (Fig. 1)
; to maintain a constant concentration of the drugs during the protracted 144-h period of the experiments, every 24 h the medium was removed and fresh solutions were added with new medium (Fig. 1)
. The 4-HC treatments were performed as recommended by Flowers et al. (17)
to avoid the toxic effects of volatile metabolites. At the end of the experiment, cells were pulsed for 6 h with 2 µCi/well of methyl-[3 H]-thymidine (Amersham Life Science), as described previously by Klement et al. (5)
. The concentration of drugs that reduced cell proliferation by 50% (IC50) as compared with controls was calculated by nonlinear regression fit of the mean values of the data obtained in triplicate experiments.
Apoptosis Measurements.
HUVEC, HMVEC-d, MDA-MB-435, T0.1, and NHDF cells were plated in 100-mm sterile dishes and continuously treated for 144 h, as described above, with 100 pM PTX, 100 pM BMS-275183, 100 pM EpoB, 100 pM 5-MP-EpoB, 100 nM 4-HC, and vehicle alone. At the end of the sixth day of treatment, cells were collected and the Cell Death Detection ELISA Plus kit (Roche) was used to quantify apoptosis as described previously (18)
All of the absorbance values (measurement wavelength, 405 nm; reference wavelength, 490 nm) were plotted as a percentage of apoptosis relative to control cells (vehicle only), which were labeled as 100%. All experiments were repeated two times with at least two replicates/sample.
Statistical Analysis.
The results (mean values ± SE) of cell proliferation, adhesion, and migration assays were subjected to statistical analysis by ANOVA, followed by the Student-Newman-Keuls test, using the GraphPad Prism© software package (version 3.0; GraphPad Software Inc.). The level of significance was set at P < 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, left). In striking contrast, a strong and dose-dependent antiproliferative effect (including at the lower concentrations) was observed when endothelial cells were continuously exposed over 144 h (Fig. 2
, right). PTX affected only endothelial cells from concentrations of 10 pM (77.3 ± 12% versus HMVEC-d control proliferation, P < 0.05; Fig. 2A
, right) to 1 nM, which showed maximum inhibition (HUVEC 14.7 ± 2.1%, HMVEC-d 9.6 ± 3.5% versus control proliferation, P < 0.05; Fig. 2A
, right), with a calculated IC50 of 51 and 96 pM for HMVEC-d and HUVEC, respectively. At the same low concentration, both breast cancer cell lines (parental and drug-resistant variant) showed no significant response, whereas the normal dermal fibroblasts were affected at 1 nM. This same trend was observed with the oral taxane BMS-275183 (Fig. 2B
, right) with a maximum inhibition of endothelial cell growth at 1 nM (HUVEC 6.3 ± 1.3%, HMVEC-d 4.5 ± 2.3% versus control proliferation, P < 0.05; Fig. 2B
, right) with an IC50 of 143 and 102 pM for HUVEC and HMVEC-d, respectively. In this case, there was the exception of a significant effect at the highest dose tested on the parental cancer cell line MDA-MB-435 (7.2 ± 1.5% versus control proliferation, P < 0.05, IC50 = 498 pM; Fig. 2B
, right) but not the multidrug-resistant T0.1 variant. Thus, a relative therapeutic antiangiogenic window appeared well defined in this case, particularly in comparison with the PTX-resistant breast cancer cell line variant. EpoB, on the other hand, showed a potent antiproliferative activity at 1 nM after 144 h (Fig. 2C
, right) on all cell lines. In this case, the range of endothelial specificity appears narrow compared with MDA-MB-435 (IC50 = 44 and 25 pM for HUVEC and HMVEC-d, respectively; IC50 = 83 for MDA-MB-435), but not if compared with T0.1 (IC50 = 517 pM); in this case, the difference remained quite significant. In contrast, for all of the compounds tested, the normal human dermal fibroblasts were affected in their proliferation only at the highest concentrations used but never at the levels observed to be effective against endothelial cells (Fig. 2
, right).
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, P < 0.05). This effect was observed at concentrations that did not affect MDA-MB-435 cancer cell growth. The IC50 in the 144-h treatments were 44.64 and 781.25 nM for HUVEC and the MDA-MB-435 cell line, respectively. As shown in Fig. 2D
, the 4-HC concentrations targeting only endothelial cells were between 1 and 100 nM (e.g., at 1 nM 77.7 ± 1% versus control proliferation, at 100 nM 43.7 ± 3.5% versus control proliferation; P < 0.05), which were in sharp contrast to the MDA-MB-435 breast cancer cell line (at 1 nM 95.6 ± 3.4% versus control proliferation, at 100 nM 83.7 ± 5.5% versus control proliferation).
Not All Antineoplastic Drugs Have a Specific Antiproliferative Activity Against Endothelial Cells.
In contrast to the above mentioned compounds, DXR and 5-MP-EpoB did not show a significant difference in their relative effects on the endothelial and the cancer cell lines (Fig. 3, A and B
, respectively) using the low-dose protracted time course regimen. The degree of the antiproliferative activity was the same against endothelial cells and cancer cells (e.g., DXR IC50 = 4.5 nM and 3.7 nM for HUVEC and MDA-MB-435, respectively; or 5-MP-EpoB IC50 = 21 pM and 19 pM for HMVEC-d and MDA-MB-435, respectively), suggesting that these drugs might act as antitumor compounds by affecting both cancer and endothelial cells at the same drug concentration. These results also show that the selectivity of endothelial cells to the other drugs we tested is not simply a function of decreased "hardiness" of such cells, compared with fibroblasts or tumor cells.
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, the assay revealed a markedly higher increase of apoptosis in the treated endothelial cells when compared with the cancer cell lines or fibroblasts, after the 6 days of treatment, especially with 100 pM PTX (+210% and +230% for HUVEC and HMVEC-d versus controls, respectively) and 100 nM 4-HC (+223% and +211% for HUVEC and HMVEC-d versus controls, respectively). In these experiments, 5-MP-EpoB did not show any selective effect on endothelial cells.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Long-term, continuous-like exposure of cells in culture to anticancer chemotherapeutic drugs has not been undertaken previously because the main objective of such experiments in the past has been to study the toxic effects of relatively high concentrations of such drugs on tumor cells. Therefore, brief exposure (e.g., 1 h), followed by assessment of effects on tumor cell viability and clonogenicity, have been typical in such experiments. The resulting IC50 values of conventional chemotherapeutic agents usually depended on numerous factors such as exposure time, pharmaceutical preparation, drug metabolism, and the type of cancer cells treated. Because of such factors, especially the short exposure times, the published effective IC50 drug concentrations on human cells of drugs such as PTX (21) , EpoB (21) , and BMS-275183 (13) tend to be much higher than the results of our experiments. In contrast, we studied the effects of protracted drug exposure using very low concentrations of drug and tested the effects of such protocols not only on tumor cells but on normal fibroblasts and vascular endothelial cells. The rationale for doing so stems from the concept of using continuous low-dose metronomic/antiangiogenic chemotherapy regimens as a means of inducing antitumor effects in vivo secondary to an effect on the endothelial cells of a tumor’s vasculature (4 , 5) . Results by Browder et al. (4) and Klement et al. (5) have shown this can cause long-term growth control of transplanted tumors with little host toxicity, and without the rapid development of drug resistance. Indeed, tumors selected for high levels of acquired resistance can be induced to respond by using metronomic/antiangiogenic chemotherapy regimens (4 , 7) , especially when they are combined with an antiangiogenic drug such as TNP-470 or anti-VEGF receptor-2 blocking antibodies (4 , 7) .
Our results are highly suggestive of an antiangiogenic window when low-dose chemotherapy is used, which becomes apparent after protracted exposure times (e.g., 144 h) where drug-containing medium is replaced on a daily basis. There was a clear trend showing the effectiveness of low concentrations of drug that had no or little effect at low dose on tumor cells or normal fibroblasts (e.g., 25–150 pM for PTX, BM-S275183, or EpoB), in contrast to microvascular endothelial cells. This was the case not only for inhibition of proliferation but also for the induction of apoptosis. Other functions such as cell migration and adhesion to extracellular matrix, which are all considered relevant to angiogenesis, are also similarly affected in a differential and selective manner (data not shown).4
Taken together, the results provide further evidence that some of the antitumor effects of anticancer chemotherapy drugs may be attributable to inhibition of tumor angiogenesis (1) . Moreover, it may be possible to significantly lower drug concentrations with the aim of reducing overall host toxicity, but without sacrificing and even increasing antitumor efficacy, as emphasized by Browder et al. (4) , Klement et al. (7) , and Bello et al. (22) . An additional benefit would be to delay acquired drug resistance (5) , and even to treat tumors that are already resistant to the very drugs used for the low-dose chemotherapy (5 , 7) , given the relative genetic stability of normal host vascular endothelial cells, in contrast to tumor cells (23) .
Whereas our experiments have dealt mainly with conventional or new cytotoxic chemotherapy drugs, the results may apply to other types of anticancer drugs as well. Indeed, we have found that BAL-9504, a geranylgeranyl-transferase inhibitor (24) , had selective antiendothelial cell effects using protracted low-dose exposures.4 We have been studying BAL-9504 in our analysis because there is evidence that similar drugs (e.g., Ras farnesyltransferase inhibitors) may have direct endothelial cell effects and, hence, might inhibit angiogenesis through such effects (25) as well as by interfering with certain tumor cell functions relevant to angiogenesis, such as VEGF production (26) .
Four other aspects of our experimental system, and results, need to be emphasized. First, the relative sensitivity of vascular endothelial cells to protracted low-dose chemotherapy may vary with the organ origin of endothelial cells. In addition, a potential weakness of our study is that we did not include types of normal cell that are ordinarily highly sensitive to chemotherapy in vivo (e.g., gut mucosal epithelial cells, hair follicle cells, or bone marrow progenitors). It is possible that such cell types may show a high degree of sensitivity to protracted exposures of low concentrations of chemotherapeutic drugs, similar to endothelial cells. This is under investigation. Second, our previous in vivo results using regimens involving frequent or continuous administration of low-dose chemotherapy (5 , 7 , 12) have emphasized the critical need for combining such regimens with a second antiangiogenic agent, such as anti-VEGF receptor-2 blocking antibody (5 , 7) , a finding confirmed by others (22 , 27, 28, 29) . For example, the intrinsic elevated sensitivity of activated endothelial cells, to low-dose chemotherapy, compared with other cells, may not be expressed as a result of the presence of high local concentrations of endothelial cell-specific survival factors such as VEGF (30, 31, 32, 33) . Such combinations may be particularly effective in inducing higher levels of apoptosis of activated endothelial cells (7) coupled with the inhibition of cell proliferation, especially when used in a protracted manner. Third, an obvious question raised by our results is why vascular endothelial cells appear to be selectively sensitive to protracted exposure of low concentrations of chemotherapeutic drugs. It is possible that the inhibition of endothelial cell growth or induction of apoptosis may not be directly mediated by the chemotherapeutic drugs tested, but rather are secondary to an event induced by the drugs (e.g., a change in expression of genes or proteins that mediate in some fashion the selective antiendothelial effects we observed). Fourth, it is interesting that some of the drugs we tested expressed potent antitumor cell activity as well as antiendothelial cell activity, when used at ultra-low concentrations in a protracted manner (e.g., EpoB). Such an agent, if it functioned in a similar manner in vivo, may be particularly useful for metronomic chemotherapy protocols because it may affect both the tumor cell and endothelial compartments in a chronic manner, and do so in a way that avoids the acute toxicities normally associated with MTD-based, tumor cell-directed, chemotherapeutic regimens.
In summary, our results add to a small but important, and growing, body of literature implicating conventional (and new) chemotherapy drugs as antiangiogenics, a property that can be enhanced by protracted exposures to low doses of drug. Our results may also be directly relevant to in vivo therapy studies using other known, or potential, antiangiogenic agents such as IFN
and endostatin where these drugs appear to have greater antiangiogenic and antitumor effects when administered frequently or continuously at low doses (34, 35, 36)
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from the NIH Service (CA41223; to R. S. K.). G. B. is financially supported by the Italian Society of Pharmacology and by an international scholarship of the Interdepartmental Centre of Clinical Pharmacology and Experimental Therapeutics, University of Pisa, generously donated by the Ente Cassa di Risparmio di Lucca. 
2 To whom requests for reprints should be addressed, at Sunnybrook and Women’s College Health Sciences Centre, Molecular and Cell Biology Research, S-218, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada. Phone: (416) 480-5711; Fax: (416) 480-5703; E-mail: robert.kerbel{at}swchsc.on.ca
3 The abbreviations used are: MTD, maximum tolerated dose; EpoB, epothilone B; 5-MP-EpoB, 5-methylpyridine EpoB; 4-HC, 4-hydroperoxycyclophosphamide; DXR, doxorubin; PTX, paclitaxel; HUVEC, human umbilical vein endothelial cell(s); HMVEC-d, human dermal microvascular endothelial cell(s); NHDF, normal human dermal fibroblast; VEGF, vascular endothelial growth factor; FBS, fetal bovine serum.
4 G. Bocci and R. S. Kerbel, unpublished observations.
Received 7/12/02. Accepted 9/27/02.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-2a therapy for life-threatening hemangiomas of infancy. N. Engl. J. Med., 326: 1456-1463, 1992.[Abstract]
-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin. Cancer Res., 5: 2726-2734, 1999.This article has been cited by other articles:
|
|
 |
|
  E. Briasoulis, P. Pappas, C. Puozzo, C. Tolis, G. Fountzilas, U. Dafni, M. Marselos, and N. Pavlidis Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer Clin. Cancer Res., October 15, 2009; 15(20): 6454 - 6461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fontana, L. Galli, A. Fioravanti, P. Orlandi, C. Galli, L. Landi, S. Bursi, G. Allegrini, E. Fontana, R. Di Marsico, et al. Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer Clin. Cancer Res., August 1, 2009; 15(15): 4954 - 4962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kreuter, M. Kropff, A. Fischaleck, K. Junker, J. Gerss, A. Heinecke, M. Lindermann, N. Reinmuth, W. E. Berdel, R. M. Mesters, et al. Prognostic relevance of angiogenesis in stage III NSCLC receiving multimodality treatment Eur. Respir. J., June 1, 2009; 33(6): 1383 - 1388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schwartz Antivascular Actions of Microtubule-Binding Drugs Clin. Cancer Res., April 15, 2009; 15(8): 2594 - 2601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Bley, W. Jochum, K. Orlowski, P. Furmanova, V. Vuong, P. M.J. McSheehy, and M. Pruschy Role of the Microenvironment for Radiosensitization by Patupilone Clin. Cancer Res., February 15, 2009; 15(4): 1335 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ma and D. J. Waxman Combination of antiangiogenesis with chemotherapy for more effective cancer treatment Mol. Cancer Ther., December 1, 2008; 7(12): 3670 - 3684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dellapasqua, F. Bertolini, V. Bagnardi, E. Campagnoli, E. Scarano, R. Torrisi, Y. Shaked, P. Mancuso, A. Goldhirsch, A. Rocca, et al. Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer J. Clin. Oncol., October 20, 2008; 26(30): 4899 - 4905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Laquente, C. Lacasa, M. M. Ginesta, O. Casanovas, A. Figueras, M. Galan, I. G. Ribas, J. R. Germa, G. Capella, and F. Vinals Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model Mol. Cancer Ther., March 1, 2008; 7(3): 638 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ma and D. J. Waxman Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib Mol. Cancer Ther., January 1, 2008; 7(1): 79 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Emmenegger, Y. Shaked, S. Man, G. Bocci, I. Spasojevic, G. Francia, A. Kouri, R. Coke, W. Cruz-Munoz, S. M. Ludeman, et al. Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice Mol. Cancer Ther., August 1, 2007; 6(8): 2280 - 2289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C.F. Moore, S. J. Green, J. R. Gralow, S. I. Bearman, D. Lew, W. E. Barlow, C. Hudis, A. C. Wolff, J. N. Ingle, H. K. Chew, et al. Intensive Dose-Dense Compared With High-Dose Adjuvant Chemotherapy for High-Risk Operable Breast Cancer: Southwest Oncology Group/Intergroup Study 9623 J. Clin. Oncol., May 1, 2007; 25(13): 1677 - 1682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhou, P. Guo, X. Wang, S. Nuthalapati, and J. M. Gallo Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 265 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Kamat, T. J. Kim, C. N. Landen Jr., C. Lu, L. Y. Han, Y. G. Lin, W. M. Merritt, P. H. Thaker, D. M. Gershenson, F. Z. Bischoff, et al. Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer Cancer Res., January 1, 2007; 67(1): 281 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]
|
|
|
|
|
|
L. Zhang, J. A.F. Hannay, J. Liu, P. Das, M. Zhan, T. Nguyen, D. J. Hicklin, D. Yu, R. E. Pollock, and D. Lev Vascular Endothelial Growth Factor Overexpression by Soft Tissue Sarcoma Cells: Implications for Tumor Growth, Metastasis, and Chemoresistance. Cancer Res., September 1, 2006; 66(17): 8770 - 8778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N.A. Bijman, G. P. van Nieuw Amerongen, N. Laurens, V. W.M. van Hinsbergh, and E. Boven Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton. Mol. Cancer Ther., September 1, 2006; 5(9): 2348 - 2357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S.W. Ng, A. Sparreboom, Y. Shaked, C. Lee, S. Man, N. Desai, P. Soon-Shiong, W. D. Figg, and R. S. Kerbel Influence of Formulation Vehicle on Metronomic Taxane Chemotherapy: Albumin-Bound versus Cremophor EL-Based Paclitaxel. Clin. Cancer Res., July 15, 2006; 12(14): 4331 - 4338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Mancuso, M. Colleoni, A. Calleri, L. Orlando, P. Maisonneuve, G. Pruneri, A. Agliano, A. Goldhirsch, Y. Shaked, R. S. Kerbel, et al. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy Blood, July 15, 2006; 108(2): 452 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Saito, M. T. Krauze, C. O. Noble, D. C. Drummond, D. B. Kirpotin, M. S. Berger, J. W. Park, and K. S. Bankiewicz Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model Neuro-oncol, July 1, 2006; 8(3): 205 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. McCarty and K. I. Block Toward a Core Nutraceutical Program for Cancer Management Integr Cancer Ther, June 1, 2006; 5(2): 150 - 171. [Abstract] [PDF]
|
|
|
|
|
|
S. D. Young, M. Whissell, J. C.S. Noble, P. O. Cano, P. G. Lopez, and C. J. Germond Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors. Clin. Cancer Res., May 15, 2006; 12(10): 3092 - 3098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. M. Dirkx, M. G. A. oude Egbrink, K. Castermans, D. W. J. van der Schaft, V. L. J. L. Thijssen, R. P. M. Dings, L. Kwee, K. H. Mayo, J. Wagstaff, J. C. A. B. ter Steege, et al. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors FASEB J, April 1, 2006; 20(6): 621 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Naumova, P. Ubezio, A. Garofalo, P. Borsotti, L. Cassis, E. Riccardi, E. Scanziani, S. A. Eccles, M. R. Bani, and R. Giavazzi The Vascular Targeting Property of Paclitaxel Is Enhanced by SU6668, a Receptor Tyrosine Kinase Inhibitor, Causing Apoptosis of Endothelial Cells and Inhibition of Angiogenesis. Clin. Cancer Res., March 15, 2006; 12(6): 1839 - 1849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ferretti, P. R. Allegrini, T. O'Reilly, C. Schnell, M. Stumm, M. Wartmann, J. Wood, and P. M.J. McSheehy Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure Clin. Cancer Res., November 1, 2005; 11(21): 7773 - 7784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shaked, U. Emmenegger, S. Man, D. Cervi, F. Bertolini, Y. Ben-David, and R. S. Kerbel Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity Blood, November 1, 2005; 106(9): 3058 - 3061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Escuin, E. R. Kline, and P. Giannakakou Both Microtubule-Stabilizing and Microtubule-Destabilizing Drugs Inhibit Hypoxia-Inducible Factor-1{alpha} Accumulation and Activity by Disrupting Microtubule Function Cancer Res., October 1, 2005; 65(19): 9021 - 9028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Emens and E. M. Jaffee Leveraging the Activity of Tumor Vaccines with Cytotoxic Chemotherapy Cancer Res., September 15, 2005; 65(18): 8059 - 8064. [Abstract] [Full Text] [PDF]
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 G. Bocci, M. Tuccori, U. Emmenegger, V. Liguori, A. Falcone, R. S. Kerbel, and M. Del Tacca Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation Ann. Onc., August 1, 2005; 16(8): 1243 - 1252. [Abstract] [Full Text] [PDF]
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P. H. Thaker, S. Yazici, M. B. Nilsson, K. Yokoi, R. Z. Tsan, J. He, S.-J. Kim, I. J. Fidler, and A. K. Sood Antivascular Therapy for Orthotopic Human Ovarian Carcinoma through Blockade of the Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptors Clin. Cancer Res., July 1, 2005; 11(13): 4923 - 4933. [Abstract] [Full Text] [PDF]
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L. Ma, G. Francia, A. Viloria-Petit, D. J. Hicklin, J. du Manoir, J. Rak, and R. S. Kerbel In vitro Procoagulant Activity Induced in Endothelial Cells by Chemotherapy and Antiangiogenic Drug Combinations: Modulation by Lower-Dose Chemotherapy Cancer Res., June 15, 2005; 65(12): 5365 - 5373. [Abstract] [Full Text] [PDF]
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B. P. Schneider and K. D. Miller Angiogenesis of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1782 - 1790. [Full Text] [PDF]
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B. Hofstetter, V. Vuong, A. Broggini-Tenzer, S. Bodis, I. F. Ciernik, D. Fabbro, M. Wartmann, G. Folkers, and M. Pruschy Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo Clin. Cancer Res., February 15, 2005; 11(4): 1588 - 1596. [Abstract] [Full Text] [PDF]
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M. Kreuter, R. Bieker, S. S. Bielack, T. Auras, H. Buerger, G. Gosheger, H. Jurgens, W. E. Berdel, and R. M. Mesters Prognostic Relevance of Increased Angiogenesis in Osteosarcoma Clin. Cancer Res., December 15, 2004; 10(24): 8531 - 8537. [Abstract] [Full Text] [PDF]
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V. R. Rozados, A. M. Sanchez, S. I. Gervasoni, H. H. Berra, P. Matar, and O. Graciela Scharovsky Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity Ann. Onc., October 1, 2004; 15(10): 1543 - 1550. [Abstract] [Full Text] [PDF]
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E. Petitclerc, R. G. Deschesnes, M.-F. Cote, C. Marquis, R. Janvier, J. Lacroix, E. Miot-Noirault, J. Legault, E. Mounetou, J.-C. Madelmont, et al. Antiangiogenic and Antitumoral Activity of Phenyl-3-(2-Chloroethyl)Ureas: A Class of Soft Alkylating Agents Disrupting Microtubules That Are Unaffected by Cell Adhesion-Mediated Drug Resistance Cancer Res., July 1, 2004; 64(13): 4654 - 4663. [Abstract] [Full Text] [PDF]
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U. Emmenegger, S. Man, Y. Shaked, G. Francia, J. W. Wong, D. J. Hicklin, and R. S. Kerbel A Comparative Analysis of Low-Dose Metronomic Cyclophosphamide Reveals Absent or Low-Grade Toxicity on Tissues Highly Sensitive to the Toxic Effects of Maximum Tolerated Dose Regimens Cancer Res., June 1, 2004; 64(11): 3994 - 4000. [Abstract] [Full Text] [PDF]
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Y. Hamano, H. Sugimoto, M. A. Soubasakos, M. Kieran, B. R. Olsen, J. Lawler, A. Sudhakar, and R. Kalluri Thrombospondin-1 Associated with Tumor Microenvironment Contributes to Low-Dose Cyclophosphamide-Mediated Endothelial Cell Apoptosis and Tumor Growth Suppression Cancer Res., March 1, 2004; 64(5): 1570 - 1574. [Abstract] [Full Text] [PDF]
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 P. B. Berger, S. H. Wilson, P. Fasseas, and J. L. Orford Reply J. Am. Coll. Cardiol., February 18, 2004; 43(4): 714 - 715. [Full Text] [PDF]
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S. M. Apte, D. Fan, J. J. Killion, and I. J. Fidler Targeting the Platelet-Derived Growth Factor Receptor in Antivascular Therapy for Human Ovarian Carcinoma Clin. Cancer Res., February 1, 2004; 10(3): 897 - 908. [Abstract] [Full Text] [PDF]
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F. Pastorino, C. Brignole, D. Marimpietri, M. Cilli, C. Gambini, D. Ribatti, R. Longhi, T. M. Allen, A. Corti, and M. Ponzoni Vascular Damage and Anti-angiogenic Effects of Tumor Vessel-Targeted Liposomal Chemotherapy Cancer Res., November 1, 2003; 63(21): 7400 - 7409. [Abstract] [Full Text] [PDF]
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 G. Bocci, G. Francia, S. Man, J. Lawler, and R. S. Kerbel Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy PNAS, October 28, 2003; 100(22): 12917 - 12922. [Abstract] [Full Text] [PDF]
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 G. Petrangolini, G. Pratesi, M. De Cesare, R. Supino, C. Pisano, M. Marcellini, V. Giordano, D. Laccabue, C. Lanzi, and F. Zunino Antiangiogenic Effects of the Novel Camptothecin ST1481 (Gimatecan) in Human Tumor Xenografts Mol. Cancer Res., October 1, 2003; 1(12): 863 - 870. [Abstract] [Full Text] [PDF]
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