BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

However, the window for human U87 tumor model is transient and only lasts about 5
days.
1.2.4 BEV in preclinical studies
Numerous studies have been conducted to investigate the pharmacological effect
of BEV in solid tumor xenograft models. Investigators have mainly focused on tumor
growth inhibition via disruption of tumor vasculature and the inhibition of tumor
metastasis.
In general, studies of the anti-VEGF effect usually employed vascular changes
and tumor growth inhibition as primary end points and have showed that BEV
significantly decreased vessel density and tumor growth regardless of tumor types. Dr.
Finn et al. showed that administration of BEV 5 mg/kg intra-peritoneal twice a week
significantly decreased microvessel density, decreased human serum alpha-fetoprotein
and delayed tumor progression for treated mice compared to the controls in a human
hepatocellular orthotopic xenograft model [82]. Dr. Okada et al. administered BEV 2
mg/kg intra-peritoneal twice a week for 8 weeks and found that BEV significantly
inhibited tumor growth by 48% in volume at the end of the experiment [83]. Meanwhile,
the intratumoral microvessel density was significantly decreased in the BEV treatment
group compared to the control group and a positive correlation was found between tumor
volume and microvessel density.
VEGF plays a critical role in the tumor angiogenesis and angiogenesis is a feature
of growth and invasion in primary neoplasms and their metastases. Furthermore, BEV
has been shown to control metastatic colorectal carcinoma, metastatic breast carcinoma,
and metastatic non–small cell lung carcinoma [84-86]. However, there are also several
case reports about more cancer metastasis after BEV treatment [87, 88]. Thus some
investigators start to assess the anti-VEGF effect on tumor metastasis. Imaizumi et al.
used a peritoneal metastasis model to determine the effect of BEV on peritoneal
dissemination from gastric cancer and showed BEV had a significant effect on peritoneal
dissemination suppression [89]. More directly, Dr. Yang et al. examined the effect of
BEV on tumor cell survival, invasiveness in vitro and metastasis in vivo [90]. The results
showed that BEV decreased in vitro growth and invasion and further suppressed in vivo
hepatic metastasis of ocular melanoma cells.
Based on the promising tumor vasculature and growth inhibitory effects of BEV
in preclinical models, the application of BEV was moved forward to clinical trials.
1.2.5 BEV in patients
Although BEV showed a significant effect on tumor vasculature changes, tumor
growth, metastasis and survival rate in preclinical studies, BEV alone only provides
modest survival benefits in patients [91]. However, it showed that anti-VEGF treatment
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