Low-dose continuous 5-fluorouracil infusion stimulates VEGF-A-mediated angiogenesis

Figures & data

Table I.  Comparison of the effects of 14-day continuous 5-FU infusion and vehicle saline on VEGF-A-mediated angiogenesis in rats

	Treatment
Variable	Saline n=14	5-FU, 75 mg/kg/w n=12
Body weight, g*	387.4±6.1	356.7±6.8
VA	14.8±2.4	28.4±4.7 (p≤0.025)
MVL	0.920±0.069	1.079±0.102
TMVL	13.6±2.2	30.6±5.0 (p≤0.02)
In. IS	10.91±0.83	14.83±1.10 (p≤0.02)
Le. MS, 0-10 percentile	n=264	n=252
range, µm	6 – 17	4 – 20 (p≤0.0001)
Le. MS, 90-100 percentile	n=264	n=252
range, µm	195 – 544	208 – 693 (p≤0.01)

*Body weight at sacrifice, i.e., the end of the treatment period. Values shown are mean±SEM.

The Le. MS values for both the 0-10 and the 90-100 percentiles were significantly elongated following 5-FU treatment.

Table

Chemotherapy (Experiment number)	Microvessel proliferation			Pattern formation and proliferation			Microvessel pattern formation
Drug, dose, duration	VA	MVL	TMVL	No. MS	No. BP	Le. MS	MVT	In. IS	In. LF
5-FU (1)
Bolus 10 mg/kg/wk	↑↑	↑	↑↑↑	↑↑	↑↑↑↑	0	0	0	0(+6%)
Bolus 30 mg/kg/wk	0	0	0	0	↑	↑*	0	0	0
Bolus 50 mg/kg/wk	0	0	↑	0	0	0	0	0	0
5- FU (2)
C.I (7 days) 20 mg/kg/wk	0	0	0
5- FU (3)
C.I. (7 days) 168 mg/kg/wk	↑↑↑↑↑	↑↑	↑↑↑↑↑
C.I. (7 days) 336 mg/kg/wk	↑↑	↑	↑↑↑
5- FU (4)
C.I. (7 days) 168 mg/kg/wk	↑↑	0	↑↑
5- FU (5)
C.I. (7 days) 168 mg/kg/wk	↑↑↑↑↑	↑↑	↑↑↑↑↑
5- FU (6)
C.I. (7 days) 168 mg/kg/wk	0	0	↑	↑↑	↑	0
C.I. (7 days) 168 mg/kg/wk	↓	↓	↓↓↓	↓	↓	↑*
+NAC 192 mg/kg/wk
5- FU (7)
C.I. (14 days) 75 mg/kg/wk	↑↑↑↑↑	↑	↑↑↑↑↑			↑↑**		↑↑↑

Drug-specific effects on angiogenesis of bolus and metronomic chemotherapy with 5-FU. C.I., continuous infusion for 7 or 14 days. The fields highlighted in gray indicate statistically significant differences compared to vehicle control. The value of 0 indicates ±9% of the value for the vehicle control. One arrow (↓ or ↑) indicates 10-19% difference from the control; two arrows (↓↓ or ↑↑), 21-30% difference from the control; three arrows (↓↓↓ or ↑↑↑), 31-40% difference from the control; four arrows (↓↓↓↓ or ↑↑↑↑), 41-50% difference from the control; and five arrows (↓↓↓↓↓ or ↑↑↑↑↑), >50% difference from the control. A single asterisk (*) indicates significant elongation of the 90-100 percentile cohort, and two asterisks (**) indicate significant elongation of the 0-10 and 90-100 percentiles. The data for experiment 1 are from [8] and the data for experiments 2-6 are from [5]. Experiment 7 is described in the current report.

VA, vascularized area; MVL, microvascular length; TMVL, total microvascular length; No. MS, number of microvessel segments; No. BP, number of microvessel branching points; In. IS, frequency of microvessel intersections. These parameters are described in detail in the Material and Methods section. The index of loop formation (In. LF), which corresponds to the frequency of interconnecting loops per unit tissue area, and the microvessel tortuosity (MVT) were assessed as described in [14] and compared to the corresponding values for the vehicle control.

Figure 1.  Graph composed of all experiments with continuous 5-FU infusion, including data from [5], in terms of total microvascular length (TMVL) presented as percent of respective experiment vehicle control. *) The 75 mg/kg/week data point (filled square) is from the here reported 14-day infusion experiment, all other are from 7 days infusion experiments (circles). **) The data point for 168 mg is composed of the arithmetic mean of 4 separate experiments, for details see Table II ±SEM.

Albertsson P, Lennernas B, Norrby K. On metronomic chemotherapy: Modulation of angiogenesis mediated by VEGF-A. Acta Oncol 2006; 45: 144–55

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