Development of a tumor-selective approach to treat metastatic cancer.
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.


RESULTS
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.
Aboody
Karen S
KS
Divisions of Hematology/Hematopoietic Cell Transplantation and Neurosciences, and Department of Professional Education, City of Hope National Medical Center, Duarte, California, United States of America. kaboody@coh.org
Bush
Rebecca A
RA
Garcia
Elizabeth
E
Metz
Marianne Z
MZ
Najbauer
Joseph
J
Justus
Kristine A
KA
Phelps
Doris A
DA
Remack
Joanna S
JS
Yoon
Karina Jin
KJ
Gillespie
Shanna
S
Kim
Seung U
SU
Glackin
Carlotta A
CA
Potter
Philip M
PM
Danks
Mary K
MK
D000818:Animals; D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000637:transplantation; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000201:enzymology / Q000637:transplantation; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary / Q000628:therapy; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
D017931:DNA Primers; D011355:Prodrugs; D011994:Recombinant Proteins; D000077146:Irinotecan; C072888:CPT-11 converting enzyme; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin