Tumor vascular normalization

Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MRL. Combretastatin A-4 phosphate as a tumor vascular-targeting agent Early effects in tumors and normal tissues. Cancer Res 1999 59 1626-1634. 

Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004 6 553-563. 

Vascular endothelial cell-derived growth factor (VEGF) was previously identified as the vascular permeability factor (VPF) by Dvorak et al. [51, 52]. Table 2 shows quantification of VEGF in various tumors and normal tissues in mice [50]. The amount of VEGF in tumor was 2- to 30- fold higher than that of normal tissues with the exception of the lung. 

Because resin microspheres carry less activity (50 Bq/ sphere) compared to glass microspheres, many more are used to deliver an adequate dose tumor. With upwards of 40 million-60 million delivered for a typical 2-GBq activity distributed in both lobes of the liver, many patients can experience temporary embolic side effects (pain, fever, nausea) which are similar but far less intense than is seen in TACE post-embolic symptoms. However, not all hepatic vascular beds can accept the number of microspheres desired from the pre-treatment planning formulae, and thus the delivery of microspheres discontinued prior to completely emptying the volume of microspheres planned. It is not the desire or plan to perform an embolic treatment, rather it is a brachyther-apy procedure and therefore it is recommended that the delivery of microspheres not cause stasis and/or reflux. Optimal implantation of microspheres is for the tumor only to have spheres, and the normal adjacent liver to be free of radiation. Once stasis has occurred, however, the normal liver arteries have also been filled with microspheres and the selectivity and therapeutic benefit to brachytherapy is lost. If the whole lobe or segment is receiving the same dose of radiation (tumor and normal liver) then external beam radiation could have been used instead. Also, many patients are selected for microsphere therapy specifically because an embolic treatment was not felt to be safe or in their best interests. 

Fig. 8.7. Vascularity observed in different tumor entities given as tumor-to-normal ratios (T/N) in MAA scintigraphy based on preliminary data. Highest T/N ratios were observed in patients with neuroendocrine tumors, followed by hepatocellular carcinoma, breast cancer and pancreatic carcinoma...

Tissue distribution of lipo-preparations. The tissue distribution of lipid microspheres in normal and pathologic animals was studied. Research into liposomes of similar size suggested that lipid microspheres accumulated preferentially in the reticuloendothelial system, inflammatory sites, or certain tumors. The distribution of lipid microspheres to these tissues has been found in our studies (7,2). Interestingly, our study showed that lipid microspheres accumulated, particularly at high concentrations, in damaged vascular walls such as atherosclerotic vascular walls. 

We have previously developed an in vivo selection method in which peptides that home to specific vascular beds are selected after intravenous administration of a phage display random peptide library [5]. This strategy revealed a vascular address system that allows tissue-specific targeting of normal blood vessels [6-8] and angiogenesis-related targeting of tumor blood vessels [3, 6, 9-12]. While the biologi-... 

---