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Safety and efficacy of a novel cannabinoid
chemotherapeutic, KM-233, for the treatment of high-grade glioma
Duntsch
C, Divi
MK, Jones
T, Zhou
Q, Krishnamurthy
M, Boehm
P, Wood
G, Sills
A, Ii
BM
Departments of Neurosurgery, The University of Tennessee Health Science
Center, Memphis, TN, USA.
Objective. To test in vitro and in vivo the safety and efficacy of a novel
chemotherapeutic agent, KM-233, for the treatment of glioma.
Methods. In
vitro cell cytotoxicity assays were used to measure and compare the
cytotoxic effects of KM-233, Delta(8)-tetrahydrocannabinol (THC), and
bis-chloroethyl-nitrosurea (BCNU) against human U87 glioma cells.
An
organotypic brain slice culture model was used for safety and toxicity
studies.
A human glioma-SCID mouse side-pocket tumor model was used to test
in vivo the safety and efficacy of KM-233 with intratumoral and
intra-peritoneal administration.
Results. KM-233 is a classical cannabinoid
with good blood brain barrier penetration that possesses a selective
affinity for the CB2 receptors relative to THC.
KM-233 was as efficacious in
its cytotoxicity against human U87 glioma as Delta(8)-tetrahydrocannabinol,
and superior to the commonly used anti-glioma chemotherapeutic agent, BCNU.
The cytotoxic effects of KM-233 against human glioma cells in vitro occur as
early as two hours after administration, and dosing of KM-233 can be cycled
without compromising cytotoxic efficacy and while improving safety.
Cyclical
dosing of KM-233 to treat U87 glioma in a SCID mouse xenograft side pocket
model was effective at reducing the tumor burden with both systemic and
intratumoral administration.
Conclusion. These studies provide both in vitro
and in vivo evidence that KM-233 shows promising efficacy against human
glioma cell lines in both in vitro and in vivo studies, minimal toxicity to
healthy cultured brain tissue, and should be considered for definitive
preclinical development in animal models of glioma.
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