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1998 Abstract: AGM-1470 REDUCES VASCULARIZATION OF THE DUCTAL PANCREATIC CARCINOMA. INTRAVITAL MICROSCOPIC OBSERVATIONS IN THE DORSAL SKIN-FOLD CHAMBER OF THE RAT: A NOVEL MODEL FOR EVALUATING ANTI-ANGIOGENETIC THERAPY. H.G. Hotz, Th. Foitzik, B. Hotz, G. Eibl, A. Menrath*, H.A. Reber°, H.J. Buhr. Depts. of Surgery, B. Franklin Medical Center, Freie Univ. Berlin, Germany and °UCLA School of Medicine, Los Angeles, CA, and *Schering AG, Berlin, Germany. 108

Abstracts
1998 Digestive Disease Week

#1012

AGM-1470 REDUCES VASCULARIZATION OF THE DUCTAL PANCREATIC CARCINOMA. INTRAVITAL MICROSCOPIC OBSERVATIONS IN THE DORSAL SKIN-FOLD CHAMBER OF THE RAT: A NOVEL MODEL FOR EVALUATING ANTI-ANGIOGENETIC THERAPY. H.G. Hotz, Th. Foitzik, B. Hotz, G. Eibl, A. Menrath*, H.A. Reber°, H.J. Buhr. Depts. of Surgery, B. Franklin Medical Center, Freie Univ. Berlin, Germany and °UCLA School of Medicine, Los Angeles, CA, and *Schering AG, Berlin, Germany.

Vascularization plays an important role for the growth and spread of tumors, and first experiences with anti-angiogenetic factors have shown promising results. However, there is little information on tumor angiogenesis under various conditions (e.g. novel anti-angiogenetic factors), since repeated direct access to the tumor for in-vivo visualization of vessels is limited. The aim of the present study was to establish a model for continuous intravital microscopic observation of a ductal pancreatic carcinoma to (1) characterize the time course and pattern of tumor vascularization, and (2) measure the effect of novel anti-angiogenetic factors.

Methods: Pancreatic tumors were grown in young rats (donors) by s.c. injection of 106 cells of the ductal pancreatic carcinoma cell line DSL 6A (purchased from ECACC, Salisbury, UK). After 6 weeks, the solid tumor was excised and tumor particles (1mm3 each) were implanted into the dorsal skin-fold chamber of 16 adult rats of the same strain. The chamber was implanted in these animals for continuous intravital microscopy together with an i.v. line one day before tumor implantation. After tumor implantation, the animals were randomly allocated in two groups. Group A (n=8) received no treatment; group B (n=8) was treated with the antiangiogenetic fumagillin analogue AGM-1470 (30 mg/kg/day s.c.; donated by Schering AG, Berlin). Beginning on day 2 after tumor implantation, animals were sedated for daily intravital microscopic observation of the tumors, which included determining the tumor size, the time course of vascularization, and the number and density of vessels after iv. injection of the plasma marker FITC-dextran 150.

Results:

Group:

First vascular
sprouts
(d.a.i.#)

Number of
sprouts
(day 7)

First per
fused vessels
(d.a.i.#)

Vessel
density
(cm-1; day 7)

Tumor size
(mm
2; day 7)

A (n = 8)

3

9.2 ± 0.7

4

54.0 ± 3.7

1.43 ± 0.2

B (n = 5*)

5

6.0 ± 1.1°

6

17.4 ± 2.1°

0.79 ± 0.1°

*3 of 8 tumors implanted in animals treated with AGM-1470 were not vascularized and underwent necrosis #d.a.i.# = day after implantation °p < 0.05 group A vs. B

Conclusion: All tumors implanted in control animals were completely vascularized within a week, while tumors in animals treated with AGM-1470 showed reduced vascularization or underwent necrosis. These observations (1) confirm the antiangiogenetic effect of AGM-1470 previously shown in other models, and (2) demonstrate that the dorsal skin-fold chamber model in the rat is not only suitable for direct continuous intravital microscopic observation of tumor vascularization but also for quantitative evaluation of anti-angiogenetic therapy. Implanting tumors into the chamber and other sites of the animals may also allow correlation of tumor angiogenesis and vascularization with tumor growth and pattern of metastasis.

Copyright 1996 - 1998, SSAT, Inc. Revised 29 June 1998.



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