pgp inhibitors Most clinically approved antiangiogenic drugs

Most clinically approved antiangiogenic drugs are aimed at blocking the action of vascular endothelial growth factor, or VEGF, which is accepted to be the most important tumor-derived angiogenic factor, stimulating proliferation and migration of endothelial cells, as well as branching of vessels (Ferrara et al., 2003). Such therapy ultimately results in nutrient deprivation of tumor as it stops formation of new capillaries, while existing ones continue to degrade with tumor growth. Moreover, it is the action of VEGF on endothelial pgp inhibitors that leads to abnormal microvessel morphology, including their increased permeability (Senger et al., 1993). Of note, normal microvessels as well demonstrate rapid increase of permeability in presence of VEGF (Fu and Shen, 2003). Anti-VEGF therapy normalizes the structures of single capillaries, in total transiently bringing tumor microvasculature to more physiologically normal state, that has been shown in numerous experiments (Gee, Procopio, Makonnen, Feldman, Yeilding, Lee, 2003, Yuan, Chen, Dellian, Safabakhsh, Ferrara, Jain, 1996). An interesting feature of antiangiogenic therapy discovered in experiments on certain mouse tumor models is that it can lead to transient increase of oxygen level inside a tumor (Ansiaux, Baudelet, Jordan, Beghein, Sonveaux, De Wever, Martinive, Grégoire, Feron, Gallez, 2005, Dings, Loren, Heun, McNiel, Griffioen, Mayo, Griffin, 2007). The conception of “normalization window” links these two phenomena together, suggesting that the normalization of microvessels leads to improvement of blood flow in tumors during first days of antiangiogenic treatment, which in its turn results in transient alleviation of hypoxia (Jain, 2005). Under constant pressure gradient, which is not affected straightforwardly by antiangiogenic therapy, blood flow is inversely proportional to the resistance of capillary system and thus improvement of blood flow must be the direct consequence of fall in microvasculature resistance. However, neutralization of VEGF brings to action a lot of physiological processes each of which by itself has different effect on it. Some of the processes indeed should lead to decrease in capillaries resistance, the most important of which is probably the reduction of interstitial pressure, increase of which in tumors occurs due to enhanced vascular permeability to blood plasma and impaired lymphatic system, that in total causes constriction of tumor capillaries (Milosevic et al., 1999). On the contrary, decrease in capillary diameters due to their normalization should provide an increase in geometric resistance, and degradation of capillaries ultimately leads to increased overall resistance. Narrowing of capillaries should also result in decrease of hematocrit, i.e., content of blood cells, which in turn should lead to decreased viscous blood resistance (Sevick and Jain, 1989), but also in diminished concentration of blood oxygen in capillaries, as it is carried by red blood cells. It is the complex interplay of all these factors that defines the change in overall resistance of tumor capillary system and affects oxygen inflow into the tumor. It is thus reasonable to assume that the result of this interaction would differ in every particular case and would depend on tumor-specific, patient-specific and site-specific factors. This idea is confirmed by the results of experiments on mouse tumor models, that, contrary to the abovementioned ones, demonstrate decrease in tumors blood perfusion in the beginning of antiangiogenic treatment (Franco, Man, Chen, Emmenegger, Shaked, Cheung, Brown, Hicklin, Foster, Kerbel, 2006, Williams, Telfer, Brave, Kendrew, Whittaker, Stratford, Wedge, 2004). Moreover, recent clinical trials show that changes in tumor perfusion and oxygenation can significantly vary even within one sample of patients indicating that these effects are strongly patient-specific (Batchelor, Gerstner, Emblem, Duda, Kalpathy-Cramer, Snuderl, Ancukiewicz, Polaskova, Pinho, Jennings, et al., 2013, Sorensen, Emblem, Polaskova, Jennings, Kim, Ancukiewicz, Wang, Wen, Ivy, Batchelor, et al., 2012).