BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

1.1.3 Strategies to improve drug penetration in solid tumors
The strategies to improve drug penetration in solid tumors mainly fall into two
categories: 1. Normalize the tumor microenvironment including tumor vasculature and
extracellular matrix (ECM). 2. Develop more effective delivery methods for drug
penetration or modifying drug property for deeper penetration.
The first strategy that investigators tried is to ameliorate the microenvironment of
solid tumors for drug penetration, normalizing the tumor vasculature and tumor matrix
[42]. Overexpression of proangiogenic molecules such as vascular endothelial growth
factor (VEGF), basic fibroblast growth factor (bFGF) and platelet-derived growth factor
(PDGF) may be the major cause of the structurally and functionally abnormal vasculature
in solid tumors [14]. Blocking these pro-angiogenic factors leads to increased apoptosis
of endothelial cells and therefore elimination of immature blood vessels, creating tumor
vessels with closer resemblance to normal vessels in structure and function [14]. The
features of tumor vasculature normalization may include the reduction of microvessel
density, interstitial fluid pressure (IFP), and hypoxia as well as the increase of blood flow
and perfusion rate [48]. Numerous studies have shown that normalization of tumor
vasculature via anti-angiogenesis therapy improves cytotoxic drug penetration in solid
tumors. Increased paclitaxel (PTX) concentration in two solid tumor tissues after
combining with BEV, an anti-VEGF monoclonal antibody, has recently been observed
accompanying the downregulation of vascular permeability [49]. In a MX-1 human
breast cancer xenograft, the intratumoral PTX concentration in mice treated with a single
dose of PTX 30 mg/kg plus a single dose of BEV 5.0 mg/kg was significantly higher than
in the tumor treated with PTX 30 mg/kg alone (5.75±0.31 µg/g vs. 4.00±0.85 µg/g). And
the PTX concentration in tumor treated with PTX 30 mg/kg plus BEV 5.0 mg/kg was
equivalent to that in the tumor treated with either 60 or 100 mg/kg of PTX alone. An
increase in PTX concentration by BEV was also observed in an A549 human lung cancer
xenograft model. In the same MX-1 model, vascular permeability in the tumor was
significantly decreased by treatment with BEV. DC101, a VEGF-receptor-2 antibody, has
been shown to normalize tumor vasculature and increase BSA penetration in several solid
tumors [50]. Combining sunitinib, an inhibitor of several tyrosine kinase receptors
(including vascular endothelial growth factor receptors, platelet-derived growth factor
receptors and stem cell factor receptor), with temozolomide significantly increases the
penetration of temozolomide in human glioma xenografts. This enhanced penetration is
associated with an improved “vascular normalization index” incorporating the
microvessel density (MVD) and protein expression of α-SMA and collagen IV [51].
Other than the normalization of vasculature, the normalization or degradation of ECM
also can improve the uptake and penetration of drugs. As discussed above, the well
organized collagen network slows the penetration rate of cytotoxic drugs. The addition of
collagenase induces a two-fold increase in tumor uptake and improves the distribution of
the monoclonal antibody TP-3 in a human osteosarcoma xenograft by degrading ECM
while decreasing IFP and microvascular pressure [52]. Furthermore, reducing the packing
density of tumor cells by chemotherapy itself can relieve the compacted ECM by killing
tumor cells, decompressing blood vessels and decreasing IFP, which results in increased
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