BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

The therapeutic agents depend on blood circulation to reach the targeted tissue, so
the pathologic vasculature is the first determinant for drug penetration in solid tumors
[38]. The distribution of the drug in tumor is governed by the blood vessel morphology
and the blood flow rate in the tumor [39]. As discussed above, the number, length,
diameter and geometric arrangement of blood vessels are irregular and the blood flow
rate is fluctuated in solid tumors. Consequently, some regions are well perfused while
other regions are totally unperfused within the same tumor [40]. Accordingly, the drug
can accumulate in one region but not access another region at all. Furthermore, cessation
of blood flow will reduce net tumor cell ‘exposure’ to the therapeutic agents in blood
circulation and even intermittent decreases in blood flow will impact on the net
distribution (AUC) of systemically administered agents [41].
Additionally, the blood vessel wall in solid tumors also affects the ability of
therapeutic drugs to diffuse universally to extra-vascular space [42]. The blood vessel
wall is heterogeneous and hyperpermeable with thick or thin basement membrane, less or
more pericytes and maximum diameter of the irregular pores [12]. The leaky wall of the
blood vessel is likely to yield higher drug uptake; however, interstitial hypertension
prevents the convective transport of drug between intra-vascular and extra-vascular
spaces [43]. Since the interstitial pressure is high throughout the core of the solid tumor
but drops dramatically in the tumor margin, the drug tends to distribute in the tumor
peripheral region rather than the center of it [23], resulting less drug penetration in the
core of solid tumors.
Lastly, the condensed interstitium and unfavorable metabolic environment
dramatically hinder the drugs from accessing tumor cells [25]. Tumor cells are highly
packed, and the extracellular matrix is compressed by tumor cells, both of which reduce
drug penetration in solid tumors [28]. Drug penetration and the efficacy of anticancer
drugs are considerably decreased in tightly packed cells compared to loosely packed cells
[44]. Similarly, the well organized and extensively interconnected collagen network in
the extracellular matrix severely affects drug movement in the interstitium [25]. The
harsh microenvironment with hypoxia and acidic pH may also impair drug penetration in
solid tumors. For example, too much hypoxia leads the hypoxia-activated prodrugs (such
as tirapazamine, AQ4N, and PR-104) to extensive metabolism, leaving no drug
remaining to penetrate to the targeting sites [45]. And weak basic drugs (such as
doxorubicin and mitoxantrone) or weak acidic drugs (such as methotrexate) have shown
slower drug penetration in acidic solid tissues [46, 47].
Thus, there are multiple determinants in solid tumors that hinder a drug from
effectively penetrating to the tumor cells and exerting its cytotoxic action. In order to
overcome this obstacle, many investigators have developed useful strategies to improve
drug penetration in solid tumors.
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