BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

over-pruned microvessel [146, 147]. In contrast, the increased intratumoral TMZ
concentration and penetration is significantly correlated to the VNI of the tumor [51,
148]. This increased intratumoral TMZ concentration is likely due to the proper tumor
vasculature normalization. Thus defining the tumor vasculature normalization window
and favorable effects of anti-angiogenic agents on the penetration of cytotoxic drugs into
solid tumors is difficult, but crucial for the success of the combination of the
anti-angiogenic agents and cytotoxic drugs regimen.
1.5.2 The effects of BEV on cytotoxic drugs disposition in solid tumors
No publications have estimated the effect of BEV on cytotoxic drug penetration in
solid tumors for clinical patients, but several papers [152, 153] demonstrate that there is
no pharmacokinetic interaction between BEV and cytotoxic drugs in the plasma of
patients with solid tumors. Thus in this section, we will only discuss the effects of BEV
on cytotoxic drugs disposition in solid tumors evaluated in preclinical studies.
In preclinical studies, Yanagisawa [49] demonstrated that the co-administration of
BEV significantly increased the intratumoral paclitaxel concentration in both murine
MX-1 human breast cancer and A547 human lung cancer xenograft models. Recently,
We also evidenced that the intratumoral penetration of TPT was enhanced as much as
81% when given 1 to 3 days after BEV, compared with when both drugs were given
concomitantly, or 7 days apart in neuroblastoma xenografts [154]. In consistent with this
observation, tumor vasculature normalization was observed within 7 days after BEV
administration and antitumor activity was also significantly enhanced when administering
TPT 3 days after BEV compared to monotherapy or concomitant administration of the
two drugs. The increased intratumoral penetration of TPT was closely associated with
normalization of the tumor vasculature. Furthermore, Davidoff (St. Jude Children’s
Research Hospital, Memphis, TN) found that the tumor vasculature normalization
window occurred between 2 to 5 days after BEV administration in the murine Rh30
rhabdomyosarcoma xenograft, and the treatment with ionizing radiation 2 or 5 days after
BEV resulted in the greatest antitumor activity [155]. In order to further investigate
whether there is a similar effect of BEV on TPT penetration in this Rh30 xenograft and
whether an optional schedule of the BEV and TPT will lead to enhanced tumor
inhibition, we proposed the current project to answer above questions and ultimately
benefit children with rhabdomyosarcoma cancer by providing a better chemotherapy
regimen. As discussed above, ARMS has a relatively low OS rate and is resistant to TPT
treatment. If we can identify the optimal schedule of BEV and TPT, and enhance the
intratumoral penetration and efficacy of TPT by using preclinical model, we may be able
to design proper clinical trials to confirm the preclinical findings and improve the OS rate
for children with ARMS.
16