Effect of VEGF receptor inhibitor PTK787/ZK222548 combined with ionizing radiation on endothelial cells and tumour growth

Abstract

SummaryThe vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dosedependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 × 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 × 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-disfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative antitumoural effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

“…Indeed, when molecules such as angiostatin Mauceri et al, 1998), endostatin (Hanna et al, 2000) or neutralising anti-human VEGF 165 antibodies (Gorski et al, 1999;Lee et al, 2000) are administered together with ionising radiation, the cytotoxic effects of the latter upon endothelial cells are potentiated in vivo, resulting in an enhanced antitumoral effect. Likewise, when radiotherapy is combined with the administration either of antibodies against VEGFR-2 or of the antiangiogenic compound TNP-470, the growth-retarding effects of radiation is potentiated (Teicher et al, 1996;Lund et al, 2000;Hess et al, 2001;Kozin et al, 2001).…”

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade

“…Also, combined treatment exerted a substantial, more than additive tumour growth delay and decrease in MVD for radiation-resistant P53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells, supporting a model of a cooperative antitumoral effect between angiogenesis inhibition and irradiation. 57 These data suggest that cooperation between androgen suppression and radiation in the treatment of prostate cancer may be the result of anti-VEGF activity by antiandrogen therapy, resulting in potentiation of ionising radiation-induced lethality. Studies that have examined factors upstream of VEGF have suggested additional benefits of VEGF-targeting by hormonal therapy.…”

Recombinant mistletoe lectin induces p53-independent apoptosis in tumour cells and cooperates with ionising radiation

“…Interestingly, combined treatment with rML (0.25 ng ml À1 ) and 2 Gy induced an at least additive antiproliferative effect in both cell populations. Experiments to determine the antiproliferative effect of rML and IR were also performed against the human p53-mutated adenocarcinoma cell line SW480, which has previously shown to be rather radiation resistant (Hess et al, 2001). Treatment with increasing doses of rML alone reduced the proliferative activity in a dose-dependent way and also showed an at least additive effect when tested in combination with IR ( Figure 5A -D).…”