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Intratumoral injection of BCNU in
ethanol (DTI-015) results in enhanced delivery to tumor--a
pharmacokinetic study
Hamstra DA, Moffat BA, Hall DE, Young JM, Desmond
TJ, Carter J, Pietronigro D, Frey KA, Rehemtulla
A, Ross BD
The Department of Radiation, The University of Michigan Medical
Center, Ann Arbor, MI 48109-0648, USA.
Solvent facilitated perfusion (SFP) has been proposed as a technique
to increase the delivery of chemotherapeutic agents to tumors.
SFP entails direct injection of the
agent into the tumor in a water-miscible organic solvent, and because
the solvent moves easily through both aqueous solutions and cellular
membranes it drives the penetration of the solubilized anticancer
agent throughout the tumor.
To test this hypothesis, we compared
the pharmacokinetics (PK) of 14C-labeled
1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat
gliomas after intravenous (IV) infusion in 90% saline--10% ethanol or
direct intratumoral (IT) injection of 14C-BCNU in 100% ethanol
(DTI-015).
Treatment with DTI-015 yielded a
peak radioactive count (Cmax) for the 14C label that was 100-1000 fold
higher in the tumor than in all other tissues in addition to a
concentration in the tumor that was 100-fold higher than that achieved
following IV infusion of 14C-BCNU.
Pathologic and auto-radiographic
analysis of tissue sections following IT injection of 14C-BCNU in
ethanol into either tumor or normal rat brain revealed both an
enhanced local volume of distribution and an increased concentration
of BCNU delivered to tumor compared to non-tumor bearing brain.
To investigate the mechanism behind
the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI
were performed on 9L tumors before and after treatment and
demonstrated a decrease in tumor perfusion following IT injection of
DTI-015.
Finally, initial PK of patient blood
samples following administration of DTI-015 into relapsed high-grade
glioma indicated a 20-fold decrease in systemic exposure to BCNU
compared to IV infusion of BCNU providing further evidence for the
enhanced therapeutic ratio observed for DTI-015.
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