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Development of a Tumor-Selective Approach to Treat Metastatic
Cancer
Karen S. Aboody1*,
Rebecca A. Bush2, Elizabeth Garcia1,
Marianne Z. Metz1, Joseph Najbauer1,
Kristine A. Justus1, Doris A. Phelps2,
Joanna S. Remack2, Karina Jin Yoon2,
Shanna Gillespie1, Seung U. Kim3,4,
Carlotta A. Glackin1, Philip M. Potter2,
Mary K. Danks2*
1Divisions
of Hematology/Hematopoietic Cell Transplantation and Neurosciences,
and Department of Professional Education, City of Hope National
Medical Center, Duarte, California, United States of America, 2Department
of Molecular Pharmacology, St. Jude Children's Research Hospital,
Memphis, Tennessee, United States of America, 3Department
of Medicine, University of British Columbia Hospital, Vancouver,
British Columbia, Canada, 4Ajou University School of
Medicine, Suwon, South Korea -- * To whom correspondence should be
addressed. E-mail: kaboody@coh.org (KSA); mary.danks@stjude.org (MKD)
-- Received: August 8, 2006; Accepted: August 10, 2006; Published:
December 20, 2006
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Background.
Patients diagnosed with metastatic cancer have almost uniformly poor
prognoses. The treatments available for patients with disseminated
disease are usually not curative and have side effects that limit the
therapy that can be given. A treatment that is selectively toxic to
tumors would maximize the beneficial effects of therapy and minimize
side effects, potentially enabling effective treatment to be
administered.
Methods
and Findings. We
postulated that the tumor-tropic property of stem cells or progenitor
cells could be exploited to selectively deliver a therapeutic gene to
metastatic solid tumors, and that expression of an appropriate
transgene at tumor loci might mediate cures of metastatic disease. To
test this hypothesis, we injected HB1.F3.C1 cells transduced to
express an enzyme that efficiently activates the anti-cancer prodrug
CPT-11 intravenously into mice bearing disseminated neuroblastoma
tumors. The HB1.F3.C1 cells migrated selectively to tumor sites
regardless of the size or anatomical location of the tumors. Mice were
then treated systemically with CPT-11, and the efficacy of treatment
was monitored. Mice treated with the combination of HB1.F3.C1 cells
expressing the CPT-11-activating enzyme and this prodrug produced
tumor-free survival of 100% of the mice for >6 months (P<0.001
compared to control groups).
Conclusions. The
novel and significant finding of this study is that it may be possible
to exploit the tumor-tropic property of stem or progenitor cells to
mediate effective, tumor-selective therapy for metastatic tumors, for
which no tolerated curative treatments are currently available.
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