Angiogenesis and vascular targeting: Relevance for hyperthermia

Figures & data

Figure 1. Schematic illustration of how the growth of most solid tumours is dependent on the development of its own neovasculature from the normal tissue vessels by the process of angiogenesis. Also shown is how vascular targeting agents (VTAs) can be used as a therapeutic approach against the tumour vasculature. They include AIAs (angiogenesis inhibiting agents) and VDAs (vascular disrupting agents), which although similar are distinctly different in their mode of action.

Table I.  Preclinical studies combining VTAs and hyperthermia.

VTA^1	Tumour model^2	Treatments^3	Reference
TNP-470	ESO-2 human oesophageal cancer	TNP-470 (30 mg/kg; s.c.; 3x/week for 2 weeks starting day 0)	34
		Waterbath heating (43°C for 30 min; shortly after each drug treatment)
	NSC-8 human gastric cancer	TNP-470 (30 mg/kg; s.c.; 3x/week for 2 weeks starting day 0)	34
		Waterbath heating (43°C for 30 min; shortly after each drug treatment)
	SCVII carcinoma	TNP-470 (100 mg/kg; s.c.; days 0 + 3 or 0, 3, 7 + 10)	35
		Waterbath heating (42° or 44°C for 30 min; day 0)
BMT	BT4An glioma*	BMT (30 mg/kg; i.p.; days 0-7 or 0-14)	37
		Waterbath heating (44°C for 60 min; days 0 or 0 + 7)
PDT	SMT-F mammary carcinoma	PDT (drug-24 hours-light on day 0)	48
		Microwave heating (40.5°, 41.5° or 44.5°C for 30 min; immediately before/after light)
	RIF-1 fibrosarcoma	PDT (drug-24 hours-light on day 0)	49
		Microwave heating (44°C for 30 min; immediately before/after light)
	R-1 rhabdomyosarcoma*	PDT (drug-24/48 hours-light on day 0)	51
		Radiofrequency heating (44°C for 30 min; 30 min after light)
	Squamous cell carcinoma	PDT (drug-83 hours-light on day 0)	50
		Microwave heating (43°C for 30 or 60 min; before/after light)
	C3H mammary carcinoma	PDT (drug-24 hours-light on day 0)	52
		Waterbath heating (43.5°C for 30, 60 or 90 min; 4 hours after light)
	C26 colon carcinoma	PDT (drug-1 hour-light on day 0)	45
		Infrared light heating (39°–43°C; simultaneously with PDT)
	DS-carcinosarcoma*	PDT (light-10 min-drug on day 0)	46, 47
		Water-filtered infrared-A radiation heating (43°C for 60 min; simultaneous with PDT)
TNF	DS-carcinosarcoma*	TNF (0.2 or 1.0 mg/kg; i.v.; days 5, 8, 11, 14, 17 + 20 after tumour implantation)	64
		Waterbath heating (43° or 44°C for 40 min; 3 hours after each TNF treatment)
	SCK mammary carcinoma	TNF (50 μg/kg; i.p.; day 0)	65
		Waterbath heating (42.5°C for 60 min; 4 hours after TNF)
ATO	SCK mammary carcinoma	ATO (2–8 mg/kg; i.p.; day 0)	59, 63
		Waterbath heating (41.5° or 42.5°C for 60 min; 2 hours after ATO)
	FsaII fibrosarcoma	ATO (2–8 mg/kg; i.p.; day 0)	59, 63
		Waterbath heating (42.5°C for 60 min; 2 or 6 hours after ATO)
VBL	BT4An glioma*	VBL (3 mg/kg; i.p.; day 0)	69
		Waterbath heating (44°C for 60 min; 0 + 3 hours before and 0, 3, 6, 12 + 24 hours after VBL)
FAA	C3H mammary carcinoma	FAA (50–200 mg/kg; i.p.; day 0)	55, 57, 73
		Waterbath heating (40.5°, 41.5° or 42.5°C for various times; from 0–120 hours after FAA)
	B16 melanoma	FAA (200 mg/kg; i.p.; day 0)	56
		Waterbath heating (43°C for 15 min; up to 8 hours before/after FAA)
DMXAA	C3H mammary carcinoma	DMXAA (1–20 mg/kg; i.p.; day 0)	60
		Waterbath heating (40.5°, 41.5° or 42.5°C for various times; from 90 min before to 6 hours after DMXAA)
CA4P	BT4An glioma*	CA4P (50 mg/kg; i.p.; day 0)	58, 62
		Waterbath heating (44°C for 60 min; up to 3 hours before and 24 hours after CA4P)
	C3H mammary carcinoma	CA4P (25–400 mg/kg; i.p.; day 0)	61
		Waterbath heating (40.5°, 41.5° or 42.5°C for various times; from 90 min before to 6 hours after CA4P)

¹The VTAs were TNP-470, batimastat, BMT; photodynamic therapy, PDT; tumour necrosis factor, TNF; arsenic trioxide, ATO; vinblastine, VBL; flavone acetic acid, FAA; 5,6-dimethylxanthenone-4-acetic acid, DMXAA; and combretastatin A-4 disodium phosphate, CA4P. ²Tumour models were either murine or rat*. ³Treatments were started when tumours had reached a specific size (day 0) or at indicated times after implantation. Drugs were injected either s.c. (subcutaneously), i.p. (intraperitoneally), or i.v. (intravenously).

Figure 2. Effect of DMXAA and heating on the radiation response of a C3H mammary carcinoma. (Top panel) Tumours were locally irradiated with graded radiation doses and the percentage of mice in each treatment group showing local tumour control 90 days after treatment recorded. Mice were given radiation alone (○); local heating (41.5°C; 60 minutes) starting 4-hours after irradiation (•); DMXAA (20 mg/kg) injected intraperitoneally 1-hour after irradiating (△); or treated with radiation, DMXAA and heat (▴). Points are from an average of 13 mice/group. (Bottom panel) TCD50 values (with 95% confidence intervals) determined from data similar to that shown in the top panel for heat alone (○); or DMXAA with heat (•). Data modified from references 61 and 78.