BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

CHAPTER 2. THE EFFECT OF BEVACIZUMAB ON THE
PHARMACOKINETICS OF TOPOTECAN IN A RH30
RHABDOMYOSARCOMA XENOGRAFT
2.1 Introduction
In order to gain sufficient nutrients and oxygen for growth, tumor cells secret and
recruit pro-angiogenic factors for the creation and maintenance of the vascular network in
solid tumors [14]. As a result, the tumor vasculature is chaotic, the blood vessel walls are
heterogeneous and the microenvironment is compact and has an interstitial hypertension
and aberrant metabolic environment─all of which can be restored by anti-angiogenic
treatments [6, 31, 53, 170]. VEGF is a key regulator of tumor angiogenesis [65, 66, 69].
It helps recruit of bone-marrow-derived progenitor cells to the primary and metastatic
sites to form a new vascular network to stimulate tumor growth. In addition, VEGF not
only promotes proliferation, migration, and invasion of endothelial cells to maintain
tumor vessel growth, but also inhibits endothelial cell apoptosis to facilitate tumor vessel
survival. Furthermore, the overexpression of VEGF is frequently observed in human
solid tumors, which is found to correlate with the extent of tumor angiogenesis,
progression and survival in patients [67, 68]. Thus, inhibiting VEGF represents a rational
strategy in treating various malignant tumors.
Rhabdomyosarcoma is the most common soft tissue sarcoma among children 0-14
years, representing nearly 50% of soft tissue sarcomas [171]. The two most common
pathologic types of RMS are embryonal RMS (ERMS) and alveolar RMS (ARMS) with
differential incidence, age pattern and body sites of occurrence [102]. ARMS grow more
aggressively than ERMS and require more intensive treatment. Therefore they have a
higher relapse incidence and worse prognostic outcome [109]. The 5 year failure-free
survival rate for ARMS (65%) is much lower than ERMS (82%) [172]. In addition, 30%
of young patients experience recurrence and 50% to 95% of these patients die of
progressive disease, even with intensified treatment [112]. So developing new agents or
new strategies to increase current agent efficacy is urgent for the treatment of RMS,
especially ARMS.
Bevacizumab (BEV) is a humanized monoclonal antibody that inhibits VEGF and
currently used to treat various cancers, including colorectal, lung, breast, kidney cancers,
and glioblastoma [173]. It is also in clinical trials for the treatment of RMS in
combination with traditional cytotoxic chemotherapy [174, 175]. However, the effect of
dosing schedule of BEV in combination with cytotoxic drugs is not well understood. The
Rh30 cell line retains the histologic appearance of ARMS [176]. VEGF is over-expressed
in the Rh30 cell line and anti-VEGF treatment has been shown to inhibit the growth of
Rh30 RMS xenograft [115]. The Rh30 cell line is more sensitive to Topotecan (TPT)
than RD cell line, characterized as ERMS cell line [116]. TPT has been actively
investigated in clinical trials and had an encouraging response rate in ARMS patients
[177]. However, preclinical and clinical studies showed that RMS is resistant to TPT as
20