Inhibition of in vivo tumour growth by the blocking of host alpha(v)beta3 and alphaII(b)beta3 integrins.

BACKGROUND: The alpha(v)beta3 integrin in the endothelial cell membrane is important for the growth and migration of capillaries into tumour tissue and is also a survival factor for these cells. The alphaII(b)beta3 (GPIIb/IIIa) integrin is responsible for platelet activation and, with concomitant release of different stored proangiogenic factors, and tumour cell-platelet interactions. MATERIALS AND METHODS: An immunodeficient nude rat model was used to study tumour growth in tibial bone, with tumour cells negative for the target alpha(v)beta3 and alphaII(b)beta3 integrins. RESULTS: Daily intraperitoneal injections of m7E3 F(ab')2 antibody fragment, blocking human and rat alpha(v)beta3 and alphaII(b)beta3 integrins, reduced the measured size of the tumours growing in the tibial bone by 35% (p = 0.012), and also the microvessel density in these tumours. The concentration of the important proangiogenic factor bFGF was significantly reduced by 41% in the treated tumours. The treatment slightly increased the time to the appearance of the tumour from 22.2 to 24.9 days, indicating a small but significant effect on the early stages of tumour growth and invasion through the bone tissue. CONCLUSION: Integrin-targeted treatment reduced tumour growth, solely targeting the host angiogenesis. This treatment strategy should be further exploited for use in combination with conventional treatment strategies, or the combined targeting of alternative antiangiogenic pathways.

Immunotoxin treatment targeted to the high-molecular-weight melanoma-associated antigen prolonging the survival of immunodeficient rats with invasive intracranial human glioblastoma multiforme.

OBJECT: The aim of this study was to target immunotoxin treatment to the high-molecular-weight melanoma-associated antigen (HMW-MAA) and thereby examine any changes in the survival of immunodeficient rats with human glioblastoma multiforme (GBM). METHODS: To target treatment specifically to human glioma cells, Pseudomonas exotoxin A (PE) was conjugated to the 9.2.27 antibody, which recognizes the HMW-MAA. Treatment of the antigen-positive glioma cell line U87MG with the resulting 9.2.27-PE caused cytotoxicity with a median inhibitory concentration of 1 ng/ml. Intratumoral 9.2.27-PE treatment of intracranial U87MG tumors in nude rats prolonged the survival of these animals by 43% compared with controls. In additional studies on the use of this targeted treatment, the authors precultured freshly dissected glioblastoma multiforme (GBM) biopsy tissue for 1 to 2 weeks. Inoculation of this tissue into the rat brain resulted in diffuse infiltrative gliomas. The markers glial fibrillary acidic protein and S100 protein were found to be expressed in the original biopsy specimens, as well as in the glioma xenografts in nude rat brains. Intratumoral immunotoxin treatment of such established tumors with 9.2.27-PE was effective and prolonged survival time from 30% to as high as 90% in animals with tumors originating from four different GBM specimens. CONCLUSIONS: Targeted treatment of highly invasive GBMs proved effective, and these results emphasize the clinical relevance of this antigen as a target molecule for immunotoxin treatment of human GBMs.