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Targeted Tubulysin B Hydrazide Conjugate for the Treatment of Luteinizing Hormone-Releasing Hormone Receptor-Positive Cancers
journal contribution
posted on 2018-05-31, 00:00 authored by Jyoti Roy, Miranda Kaake, Madduri Srinivasarao, Philip S LowThe targeted delivery of chemotherapeutic
agents to receptors that
are overexpressed on cancer cells has become an attractive strategy
to concentrate drugs in cancer cells while avoiding uptake by healthy
cells. Luteinizing hormone-releasing hormone receptor (LHRH-R) has
attracted considerable interest for this application, since LHRH-R
is upregulated in ∼86% of prostate cancers, ∼80% of
endometrial cancers, ∼80% of ovarian cancers, and ∼50%
of breast cancers, but virtually absent from normal tissues. Although
LHRH and related peptides have been used to deliver cytotoxic drugs
to LHRH-R overexpressing cancer cells, they have suffered from off-target
delivery of the therapeutic agents to the liver and kidneys. To reduce
such unwanted uptake by peptide scavenger receptors in the liver and
kidneys, we have explored the use of a nonpeptidic LHRH-R antagonist
(NBI42902) to construct an LHRH-R targeted tubulysin conjugate (BOEPL-L3-TubBH).
In vitro studies with BOEPL-L3-TubBH demonstrate that the conjugate
can kill LHRH-R expressing triple-negative breast cancer cells (MDA-MB-231
cells) with low nanomolar IC50. Related studies on tumor-bearing
mice further reveal that the same conjugate can eradicate MDA-MB-231
solid tumors without any measurable side-effects, yielding mice that
gain weight during therapy and show no evidence of tumor recurrence
for at least 5 weeks after termination of treatment. That these complete
responses are LHRH-R targeted was then established by showing that
identical treatment of receptor-negative (SKOV3) tumors yields no
antitumor response. Overall, these data provide a proof-of-concept
that LHRH-R specific targeting of an extremely toxic drug like tubulysin
B can treat LHRH-R positive tumors without causing significant toxicity
to healthy cells.
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Luteinizing Hormone-Releasing Hormone Receptor-Positive CancersSKOVTargeted Tubulysin B Hydrazide ConjugateBOEPL-L 3-TubBHcancer cellsLuteinizing hormone-releasing hormone receptornonpeptidic LHRH-R antagonisttumorNBIpeptide scavenger receptorsLHRH-R overexpressing cancer cellstriple-negative breast cancer cellsMDA-MB -231 cellsnanomolar IC 50
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