Vascular targeted therapies in oncology

Abstract

Neovascularization is intimately involved in tumor survival, progression, and spread, factors known to contribute significantly to treatment failures. Thus, strategies targeting the tumor blood vessel support network may offer not only unique therapeutic opportunities in their own right, but also novel means of enhancing the efficacies of conventional anticancer treatments. This article reviews one such therapeutic approach directed at the tumor blood vessel support network. Vascular disrupting therapies seek the destruction of the established neovasculature of actively growing tumors. The goal of these therapies is to cause a rapid and catastrophic shutdown in the vascular function of the tumor in order to arrest the blood flow and produce tumor cell death as a result of oxygen and nutrient deprivation and the build up of waste products.

Fig. 1

Effect of VDA treatment on patent tumor blood vessels in KHT sarcomas. Tumor-bearing mice were treated with 100 mg/kg CA4P (a), 100 mg/kg ZD6126 (b), 100 mg/kg MN029 (c), or 25 mg/kg OXi4503 (d), and at various times thereafter, the numbers of functional blood vessels were determined by using the fluorescent dye Hoechst 33342. Results are the means±SE of three to five tumors. From Siemann and Horsman 2008; with permission

Fig. 2

Tumor blood perfusion measured by using dynamic contrast-enhanced magnetic resonance imaging after treatment with a single dose of CA4P (100 mg/kg) or OXi4503 (25 mg/kg). Data points represent changes in tumor perfusion in individual mice as a function of time after treatment. Values given are the median group response as a function of time after treatment. From Salmon and Siemann 2006; with permission

Fig. 3

Histological assessment of KHT-sarcoma-bearing mice treated with ZD6126. a Hematoxylin and eosin staining of control KHT tumors showing little necrosis. b By 24 h after treatment with ZD6126 (150 mg/kg), extensive areas of necrosis are seen with viable tumor cells present only at the tumor periphery (arrows). c, d The viable rim (arrows) is more readily apparent at higher magnification. From Siemann 2002; with permission

Fig. 4

Survival of clonogens in KHT sarcomas 24 h after treatment with a range of doses of radiation given either alone (open symbols) or in combination with a 2.5-mg/kg dose of OXi4503 (closed symbols). In the combination treatment, OXi4503 was administered 1 h after radiotherapy. Data are the means±SE of three to nine tumors. From Siemann and Horsman 2008; with permission

Fig. 5

Response of KSY-1 xenografts in mice treated with ZD6474 (Zactima) and ZD6126 either alone or in combination. The antiangiogenic ZD6474 (25 mg/kg) was administered orally on a daily basis, starting on the day that the tumors reached a size of 200 mm³, for a period of 5 days. The VDA ZD6126 was given intraperitoneally on days (D) 1, 3 and 5 at a dose of 100 mg/kg. In the combination group, ZD6126 was given 1 h after ZD6474, on days when both agents were administered. The results show the growth of the median tumors of groups of eight mice. From Siemann and Shi 2004; with permission