| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Departments of Surgery [T. A. D., I. H. M. B. R., E. D. R., T. J. M. V. v. V.] and Internal Medicine [T. A. D., M. F. B. G. G., E. E. V.], Laboratory of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
In analogy herewith, liver regeneration after extensive hepatic resection is accompanied by a similar peak in local growth factor production, including proangiogenic factors, eliciting proliferative responses along a variety of auto- and paracrine pathways (4, 5, 6, 7, 8, 9) . As a consequence, it has been suggested that residual "dormant" micrometastases in the liver remnant might also display stimulated growth after major hepatic resection. Recent experimental data appear to support this concept (10, 11, 12) . The role of angiogenesis under these circumstances is unknown. One could speculate that antiangiogenic treatment to prevent outgrowth of liver metastases might be problematic because of the overwhelming number of secondary tumor cell deposits. These deposits each produce their own proangiogenic microenvironment in a host organ where angiogenesis dependency has been demonstrated to differ from that in s.c. deposits (13) . Moreover, the local secretion of large amounts of growth factors after partial hepatectomy may present additional loss of effectiveness of angiogenesis inhibitors. On the other hand, there is sufficient experimental evidence that antiangiogenic treatment using exogenously administered, plasminogen-derived human angiostatin effectively inhibits outgrowth of pulmonary metastases (3) . In addition, angiostatin causes regression of existing macroscopic solid tumors, supporting our hypothesis that angiostatin does inhibit accelerated metastatic outgrowth in regenerating liver (3 , 14 , 15) .
To test this hypothesis, optimal administration of angiostatin is a
prerequisite. Hitherto, most animal studies on angiostatin have used a
twice-daily s.c. treatment schedule. The half-life of human angiostatin
in mice is around 4–6 h (1)
. This implies that
twice-daily injections do not allow for continuous suppression of
angiogenesis. Accordingly, we have previously demonstrated that
twice-daily bolus injections with IFN-
at a sublethal concentration
only partially suppressed angiogenesis, whereas continuous infusion of
IFN- at half the daily dose of the bolus injections completely
inhibited angiogenesis (16)
. The idea that antitumoral
effects could be improved by continuous administration of an
antiangiogenic peptide (TNP-470), instead of intermittent
administration, was also supported by Yamaoko et al.
(17)
.
The present study was undertaken to define the optimal route of administration of angiostatin and to evaluate the antitumoral efficacy of such treatment in experimental colorectal hepatic metastases in resting liver, as well as in liver regeneration after major partial hepatectomy. We show that continuous administration of angiostatin significantly improves its antiangiogenic and antitumoral effects when compared with twice-daily s.c. bolus injections. Furthermore, continuous administration of angiostatin was able to suppress accelerated growth of colorectal liver metastases in a regenerating liver.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
Angiostatin Production
Human angiostatin was generated as described by O’Reilly
et al. (1)
using minor modifications. Briefly,
recovered outdated human plasma was diluted 2:1 with PBS, supplemented
with 3 mM EDTA, warmed up (37°C), and filtered
(0.1 mm). The plasma was then applied to a lysine-Sepharose column
(Pharmacia, Uppsala, Sweden) at room temperature. After washing the
column with 0.5 M phosphate buffer, plasminogen
was eluted with 0.2 M prewarmed (37°C)
-aminocaproic acid at pH 7.4. SDS-PAGE of the eluant revealed one
band of apparent Mr 92,000
corresponding to plasminogen. The eluant was dialyzed against
demi-water (MWCO: 6–8000 Spectra/Por; >4 x 107 dilution; 4°C), followed by proteolytic
digestion (12 h at 37°C; 120 rpm) with porcine pancreatic elastase
(Calbiochem, San Diego, CA) in a concentration of 0.8 unit/mg
plasminogen using a shaker (24 h at 37°C; 120 rpm). Next, the
solution was applied to a lysine-Sepharose column again that had been
equilibrated with a salt solution pH 7.4 (0.5 M
NaCl, 0.2 M -ACA, 0.03 M
NaH2PO4, 0.02
NaN3, and 0.1% Triton). Furthermore, the column
was reequilibrated with a 30 mM phosphate buffer
at pH 7.4. Finally, angiostatin was eluted with 0.2
mM -ACA and dialyzed against demi-water (MWCO:
6–8000 Spectra/Por; >4 x107 dilution).
SDS-PAGE revealed three distinct bands of approximately
Mr 40,000,
Mr 42,000, and
Mr 45,000, resembling the triplet
first described by O’Reilly et al. (1)
. After
freeze-drying, angiostatin was dissolved in PBS (175 mg/ml) and stored
at -80°C.
Animals
Male Balb/c mice, 8–10 weeks of age, were used in all
experiments and were purchased from the General Animal Laboratory,
University Medical Center Utrecht. Animals were maintained under
specific pathogen-free conditions, food and water ad
libitum, and kept on a 12-h light/12-h dark cycle. Experiments
were performed according to the guidelines of the Utrecht Animal
Experimental Committee, University Medical Center Utrecht.
Cornea Neovascularization Assay
Antiangiogenic effects and dose dependency of angiostatin were
tested in cornea neovascularization assay as described previously,
using minor modifications (18)
. Briefly, mice
(n = 8 eyes/group) were anesthetized using a
mixture of Hypnorm (0.3 mg/mouse i.p.; Janssen-Cilag, Brussels,
Belgium) and Dormicum (12.5 mg/mouse i.p.; Roche, Brussels, Belgium).
In addition, both corneas were anesthetized locally with 4 mg/ml
oxybuprocaine (0.4%). Corneal micropockets were created with surgical
blade number 10 and a pair of microscopic tweezers, followed by
implantation of a 
100 ng basic fibroblast growth factor (Life
Technologies, Inc., Rockville, MD) containing sucrose aluminum
sucralfate pellet coated with Hydron (IFN Sciences, New Brunswick, NJ).
To prevent corneal infection, Aknemycin (Merck-Belgolabo NV, Overijse,
Belgium) was applied to the cornea. The corneas of mice were examined
daily by microscope. The surface area of newly formed blood vessels was
determined using a formula (0.2 x 
x maximal vessel length x clock hours) described by
Kenyon et al. (19)
. The experiment was ended
when in untreated animals the newly formed blood vessels had reached
the pellet (6 days after implantation of pellets).
Tumor Models
s.c. Tumor.
Mice (n = 7/group) received a s.c. injection
of 106 C-26 cells in 100 µl of PBS. Tumor
diameters were determined daily by caliper, and tumor volume was
calculated by the formula: width2 x length x 0.52. The experiment was ended after 14 days
when the tumors of control mice reached a volume that started to affect
the quality of life.
Liver Metastases.
Liver metastases were induced as follows. After anaesthetizing mice
(n = 7/group), a transverse incision in the
left flank was performed, exposing the spleen, followed by intrasplenic
injection of 105 C-26 tumor cells in 100 µl of
PBS using a 27-gauge needle (20)
. A visible "paling"
of the spleen and the lack of bleeding were the criteria for a
successful inoculation. Five min later, the spleen was removed to
prevent growth of tumor cells in the spleen. In this model, metastases
are confined to the liver (data not shown). Seven and 14 days after
tumor inoculation, mice were sacrificed, and wet liver weight was
measured. Then, left lateral and median liver lobes were frozen in
liquid nitrogen and stored at -80°C until determination of the
hepatic replacement area.
Accelerated Intrahepatic Tumor Growth.
Five min after intrasplenic injection of 105 C-26
tumor cells, the spleen was resected; 5 min later, the left lateral and
caudal liver lobes were ligated and resected, resulting in a partial
hepatectomy of 70%. Tumor growth was evaluated on days 7 and 14. Mice
were randomized into four groups: tumor growth in resting liver
(n = 12); tumor growth in resting liver + angiostatin treatment (n = 11); tumor
growth in regenerating liver (n = 6); and
tumor growth in regenerating liver + angiostatin treatment
(n = 6).
Intrahepatic tumor angiogenesis was evaluated by sectioning 10 standardized cryosections (5 µm) of each liver lobe and reacting with monoclonal antibodies (MEC 13.3) against CD31 and counterstained with hematoxylin (21) . Furthermore, in each section the intrahepatic metastases were encircled using a digitalized pen that was connected to a light microscope unit (Axioskop; Zeiss, Oberkochen, Germany) and video camera (Sony CCD/RGB color video camera; Hamburg, Germany). In this way, microscopic images were transferred into a computer frame store. Calculation of the hepatic replacement area, i.e., the ratio of tumor volume/total liver volume (%), was calculated using software of Videoplan 2.2 (Kontron Elektronik GmbH, Eching, Germany).
|
Treatment Schedules |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
Antiangiogenic effects and dose response were tested in the cornea neovascularization assay for 6 days using three daily doses (1, 10, and 100 mg/kg; n = 8/group). The Alzet 2001 pump was used. In all tumor models, a cumulative daily dose of 100 mg/kg was used. Furthermore, in all of the pump groups in the tumor models, the Alzet 2002 type was used.
|
Statistical Analysis |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
. In the bolus group, inhibition was dose dependent: twice-daily
injection with 1, 10, and 100 mg/kg/day resulted in 14.02, 33.38, and
72.10% inhibition, respectively. Furthermore, continuous
administration of angiostatin resulted in a dose-dependent inhibition,
which was significantly greater than bolus injection at all dose
levels: 22.71, 67.07, and 92.68% inhibition. No corneal edema was
seen. Histological examination revealed no signs of inflammation.
|
s.c. Tumor.
Fourteen days after tumor cell inoculation, tumors of the control group
had reached a volume of 1848 ± 84
mm3 (Fig. 2)
. In mice treated twice-daily with angiostatin, the mean s.c. tumor
volume was 919 ± 94 mm3. Near
total suppression of tumor growth was observed in mice that received
angiostatin continuously (tumor volume = 104 ± 16 mm3).
|
. In control animals, the respective hepatic replacement areas were
59.3 ± 7.5% and 97 ± 2% on
POD7 and POD14. In the
bolus group, they were 43.3 ± 8.1%
(POD7) and 81 ± 10.1%
(POD14), respectively, whereas maximal inhibition
of tumor growth was observed in the pump group, with hepatic
replacement areas of 12 ± 4.6% on
POD7 and 43 ± 5.3% on
POD14.
|
|
Accelerated Tumor Growth in Regenerating Liver and Angiostatin |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
. On POD7, the hepatic replacement area of
control mice carrying colorectal liver metastases was 24.6 ± 4.1%, whereas in the hepatectomized group, the hepatic
replacement area had more than doubled: 53 ± 3.2%
(Fig. 5)
. This discrepancy between nonhepatectomized and hepatectomized groups
had disappeared on POD14 (64 ± 7.1% and 68 ± 3.7%, respectively). Accelerated tumor
growth in regenerating liver was inhibited significantly by
angiostatin. On POD7, the hepatic replacement
area of nontreated hepatectomized mice and angiostatin-treated
hepatectomized mice was 53 ± 3 and 20.8 ± 1.4%, respectively. Seven days later, on
POD14, the hepatic replacement area in
angiostatin-treated mice was 34 ± 1%, i.e.,
approximately half that in nontreated control mice (68 ± 3.7%).
|
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
As reported by others, we confirmed that performing a partial hepatectomy leads to accelerated intrahepatic tumor growth (22 , 23) . Because angiostatin strongly inhibited liver metastases in resting liver, we expected that angiostatin could suppress the accelerated outgrowth of liver metastases in regenerating liver as well. However, we did not expect that antitumoral effects of angiostatin would be as strong as the inhibition of liver metastases in a resting liver. Surely, in a regenerating liver, both remnant liver and colorectal liver metastases contribute to local expression of growth factors, whereas in a resting liver, only the tumor contributes to up-regulation of local growth factors. This is supported by others; vascular endothelial growth factor, one of the major proangiogenic factors, is up-regulated in colorectal hepatic metastases in resting (24 , 25) and in remnant hepatocytes in regenerating liver (26) . On POD7, no significant differences could be observed between inhibition of tumor growth of colorectal metastases in resting (58% inhibition) and regenerating liver (60% inhibition). But on POD14, inhibition of tumor growth of metastases was significantly stronger in the resting liver (63% inhibition) compared with the regenerating liver (49% inhibition; P < 0.05). This might be explained by the concept that compared with tumor growth in a resting liver, in a regenerating liver the local imbalance of growth factors may be shifted more to the side of the proangiogenic factors. One way to overcome this problem could be to further increase the total daily dose of angiostatin. Furthermore, the effect of angiostatin, or any antiangiogenic treatment, on liver regeneration after partial hepatectomy deserves attention. In preliminary experiments, we have found that angiostatin, in addition to an antitumor effect, reduces the rate of physiological liver regeneration.4
It is important to note that antitumor activity of angiostatin was measured differently in the s.c. and liver metastases model; liver metastases were measured by surface area (mm2), whereas sc. tumor growth was evaluated using tumor volume (mm3). It is a mathematical fact that any difference in tumor growth between control and test groups will be more strongly exhibited using volume then area. Therefore, it appears that angiostatin is less effective in the liver metastases in comparison with s.c. tumors. The sc. injection of tumor cells in the s.c. dorsal skinfold results in a localized tumor deposit containing 106 tumor cells, whereas in the liver model, an intrasplenic injection with 105 tumor cells results in a large number of intrahepatic tumor deposits. The liver metastases may all grow to 1–2 mm2 without neovascularization. This results in a substantial tumor growth not affected by antiangiogenesis treatment. However, all described models demonstrate that continuous administration compared with twice-daily injections is crucial for inhibiting angiogenesis and tumor growth.
The role of antiangiogenic treatment for colorectal hepatic micrometastases after partial hepatectomy is unclear. In agreement to our results, Tanaka et al. (27) reported previously that the angiogenesis inhibitor TNP-470 inhibited growth of colorectal liver metastases in rabbits. Our findings are relevant to the future use of antiangiogenic agents in cancer patients. In this study, we focused on colorectal hepatic metastases. The optimal clinical use of angiogenesis inhibitors may be in the adjuvant setting (28) . Patients at risk for recurrence, either after complete surgical resection of the primary tumor/hepatic metastases or after successful chemotherapy or radiation therapy, could be candidates for antiangiogenic treatment in an attempt to impose dormancy on residual clinically undetectable micometastases. Continuous suppression appears to be crucial in preventing the outgrowth of tumors. This may be done by continuous administration of these agents by ambulatory infusion pumps, by modulating antiangiogenic drugs to increase their plasma half-lives, or by new approaches such as gene therapy.
In conclusion, plasminogen-derived human angiostatin is a very potent antiangiogenic and antitumoral agent. Its biological effects can be improved remarkably by continuous administration instead of only twice-daily. Furthermore, angiostatin might play an important role as an adjuvant antitumoral agent in patients subjected to partial hepatectomy for colorectal hepatic metastases.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 This work was supported by the Wijnand M. Pon
Foundation (to T. A. D.), the Netherlands Digestive Diseases
Foundation Grant WS 96-29 (to T. A. D.), and the Dutch Cancer Society
Grant 99-2114 (to M. F. B. G. G.). 
2 To whom requests for reprints should be
addressed, at Department of Internal Medicine, Division of Medical
Oncology, Laboratory of Medical Oncology, University Medical Center,
P. O. Box 85500, 3508 GA Utrecht, the Netherlands. Phone:
31-30-2506265; Fax: 31-30-2523741; E-mail: E.E.Voest{at}digd.azu.nl
3 The abbreviations used are: POD7 or
POD14, postoperative day 7 or 14, respectively.
4 T. A. Drixler, M. F. B. G. Gebbink, T. J. M. V. v. Vroonhoven, E. E. Voest, and I. H. M. Borel Rinkes. Does angiostatin affect physiological angiogenesis?, manuscript in preparation.
Received 9/ 8/99. Accepted 1/18/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSTreatment SchedulesStatistical AnalysisRESULTSAccelerated Tumor Growth in...DISCUSSIONREFERENCES |
|---|
may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc. Natl. Acad. Sci. USA, 86: 1558-1562, 1989.. Br. J. Surg., 82: 129-132, 1995.[Medline]
This article has been cited by other articles:
|
|
 |
|
  C.R. Dass, T.M.N. Tran, and P.F.M. Choong Angiogenesis Inhibitors and the Need for Anti-angiogenic Therapeutics Journal of Dental Research, October 1, 2007; 86(10): 927 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Rademaker-Lakhai, L. V. Beerepoot, N. Mehra, S. A. Radema, R. van Maanen, J. S. Vermaat, E. O. Witteveen, C. M. Visseren-Grul, L. Musib, N. Enas, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C {beta}-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4474 - 4481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, J. Xu, J. Lawler, E. Terwilliger, and S. Parangi Adeno-Associated Virus-Mediated Antiangiogenic Gene Therapy with Thrombospondin-1 Type 1 Repeats and Endostatin Clin. Cancer Res., July 1, 2007; 13(13): 3968 - 3976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D.W. van der Bilt, M. E. Soeters, A. M.M.J. Duyverman, M. W. Nijkamp, P. O. Witteveen, P. J. van Diest, O. Kranenburg, and I. H.M. Borel Rinkes Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases Am. J. Pathol., April 1, 2007; 170(4): 1379 - 1388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Michaud-Levesque, M. Demeule, and R. Beliveau In vivo inhibition of angiogenesis by a soluble form of melanotransferrin Carcinogenesis, February 1, 2007; 28(2): 280 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kurup, C.-W. Lin, D. J. Murry, L. Dobrolecki, D. Estes, C. T. Yiannoutsos, L. Mariano, C. Sidor, R. Hickey, and N. Hanna Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University Ann. Onc., January 1, 2006; 17(1): 97 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-K. Yu, J.-S. Kim, H.-J. Lee, J.-H. Ahn, S.-K. Lee, S.-W. Hong, and Y. Yoon Suppression of Colorectal Cancer Liver Metastasis and Extension of Survival by Expression of Apolipoprotein(a) Kringles Cancer Res., October 1, 2004; 64(19): 7092 - 7098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nakajima, T. Gotanda, H. Uchimiya, T. Furukawa, M. Haraguchi, R. Ikeda, T. Sumizawa, H. Yoshida, and S.-i. Akiyama Inhibition of Metastasis of Tumor Cells Overexpressing Thymidine Phosphorylase by 2-Deoxy-L-Ribose Cancer Res., March 1, 2004; 64(5): 1794 - 1801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Turner, A. L. Harris, S. Melmed, and J. A. H. Wass Angiogenesis in Endocrine Tumors Endocr. Rev., October 1, 2003; 24(5): 600 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Beerepoot, E. O. Witteveen, G. Groenewegen, W. E. Fogler, B. K. L. Sim, C. Sidor, B. A. Zonnenberg, F. Schramel, M. F. B. G. Gebbink, and E. E. Voest Recombinant Human Angiostatin by Twice-Daily Subcutaneous Injection in Advanced Cancer: A Pharmacokinetic and Long-Term Safety Study Clin. Cancer Res., September 15, 2003; 9(11): 4025 - 4033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Stoeltzing, W. Liu, N. Reinmuth, A. Parikh, S. A. Ahmad, Y. D. Jung, F. Fan, and L. M. Ellis Angiogenesis and Antiangiogenic Therapy of Colon Cancer Liver Metastasis Ann. Surg. Oncol., August 1, 2003; 10(7): 722 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Capillo, P. Mancuso, A. Gobbi, S. Monestiroli, G. Pruneri, C. Dell'Agnola, G. Martinelli, L. Shultz, and F. Bertolini Continuous Infusion of Endostatin Inhibits Differentiation, Mobilization, and Clonogenic Potential of Endothelial Cell Progenitors Clin. Cancer Res., January 1, 2003; 9(1): 377 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. M. Schellens and M. J. Ratain Endostatin: Are the 2 Years Up Yet? J. Clin. Oncol., September 15, 2002; 20(18): 3758 - 3760. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Eder Jr, J. G. Supko, J. W. Clark, T. A. Puchalski, R. Garcia-Carbonero, D. P. Ryan, L. N. Shulman, J. Proper, M. Kirvan, B. Rattner, et al. Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily J. Clin. Oncol., September 15, 2002; 20(18): 3772 - 3784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Herbst, K. R. Hess, H. T. Tran, J. E. Tseng, N. A. Mullani, C. Charnsangavej, T. Madden, D. W. Davis, D. J. McConkey, M. S. O'Reilly, et al. Phase I Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors J. Clin. Oncol., September 15, 2002; 20(18): 3792 - 3803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hlatky, P. Hahnfeldt, and J. Folkman Clinical Application of Antiangiogenic Therapy: Microvessel Density, What It Does and Doesn't Tell Us J Natl Cancer Inst, June 19, 2002; 94(12): 883 - 893. [Full Text] [PDF]
|
|
|
|
|
|
E. A. te Velde, E. E. Voest, J. M. van Gorp, A. Verheem, J. Hagendoorn, M. F. Gebbink, and I. H. Borel Rinkes Adverse Effects of the Antiangiogenic Agent Angiostatin on the Healing of Experimental Colonic Anastomoses Ann. Surg. Oncol., April 1, 2002; 9(3): 303 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Streit, A. E. Stephen, T. Hawighorst, K. Matsuda, B. Lange-Asschenfeldt, L. F. Brown, J. P. Vacanti, and M. Detmar Systemic Inhibition of Tumor Growth and Angiogenesis by Thrombospondin-2 Using Cell-based Antiangiogenic Gene Therapy Cancer Res., April 1, 2002; 62(7): 2004 - 2012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Drixler, I. H. M. B. Rinkes, E. D. Ritchie, F. W. Treffers, T. J. M. V. van Vroonhoven, M. F. B. G. Gebbink, and E. E. Voest Angiostatin Inhibits Pathological but Not Physiological Retinal Angiogenesis Invest. Ophthalmol. Vis. Sci., December 1, 2001; 42(13): 3325 - 3330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Kisker, C. M. Becker, D. Prox, M. Fannon, R. D'Amato, E. Flynn, W. E. Fogler, B. K. L. Sim, E. N. Allred, S. R. Pirie-Shepherd, et al. Continuous Administration of Endostatin by Intraperitoneally Implanted Osmotic Pump Improves the Efficacy and Potency of Therapy in a Mouse Xenograft Tumor Model Cancer Res., October 1, 2001; 61(20): 7669 - 7674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Kerbel Clinical Trials of Antiangiogenic Drugs: Opportunities, Problems, and Assessment of Initial Results J. Clin. Oncol., September 15, 2001; 19(90001): 45s - 51. [Full Text] [PDF]
|
|
|
|
|
|
A. L. Feldman, H. R. Alexander, S. M. Hewitt, D. Lorang, C. E. Thiruvathukal, E. M. Turner, and S. K. Libutti Effect of Retroviral Endostatin Gene Transfer on Subcutaneous and Intraperitoneal Growth of Murine Tumors J Natl Cancer Inst, July 4, 2001; 93(13): 1014 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Indraccolo, M. Morini, E. Gola, F. Carrozzino, W. Habeler, S. Minghelli, L. Santi, L. Chieco-Bianchi, Y. Cao, A. Albini, et al. Effects of Angiostatin Gene Transfer on Functional Properties and in Vivo Growth of Kaposi's Sarcoma Cells Cancer Res., July 1, 2001; 61(14): 5441 - 5446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guba, G. Cernaianu, G. Koehl, E. K. Geissler, K.-W. Jauch, M. Anthuber, W. Falk, and M. Steinbauer A Primary Tumor Promotes Dormancy of Solitary Tumor Cells before Inhibiting Angiogenesis Cancer Res., July 1, 2001; 61(14): 5575 - 5579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Moser, D. J. Kenan, T. A. Ashley, J. A. Roy, M. D. Goodman, U. K. Misra, D. J. Cheek, and S. V. Pizzo Endothelial cell surface F1-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin PNAS, May 24, 2001; (2001) 131067798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Stellmach, S. E. Crawford, W. Zhou, and N. Bouck Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor PNAS, February 27, 2001; 98(5): 2593 - 2597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Moser, D. J. Kenan, T. A. Ashley, J. A. Roy, M. D. Goodman, U. K. Misra, D. J. Cheek, and S. V. Pizzo Endothelial cell surface F1-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin PNAS, June 5, 2001; 98(12): 6656 - 6661. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
, control group. All dose levels differ significantly
from the control group. At a dose level of 1 mg/kg/day, the difference
between the bolus and pump group was not significant
(P = 0.1778). At the dose levels of 10
and 100 mg/kg/day, the difference between the bolus and pump groups was
significant (P < 0.001 and
P = 0.001, respectively).
Bars, SE.
, PBS
control (n = 6); 
, pump
(n = 7; angiostatin, 100 mg/kg/day); 
, bolus group treated with angiostatin (100 mg/kg body
weight/day); 
, pump group treated with angiostatin (100 mg/kg body
weight/day). Tumor growth is expressed as a percentage using the
hepatic replacement area on histological slides. Significantly
different from control values: *, P < 0.001; **, P < 0.05.
POD7 and POD14 values between bolus and pump
groups were significantly different: P < 0.001. Bars, SE.
, tumor growth in regenerating liver (n = 6);