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Gene Therapy To Protect Hematopoietic Cells From Cytotoxic
Chemotherapy In A Clinically Relevant Large Animal Model
Hans-Peter Kiem, Tobias Neff, Brian C. Beard, Laura J.
Peterson, Bobbie M. Thomasson, Jess Thompson
Fred Hutchinson Cancer Research
Ctr., Seattle, WA.
Backround. Myelosuppression is a common dose-limiting toxicity in the treatment
of cancer with intensive chemotherapy, often leading to significant dose
reductions.
However, there is an increasing body of evidence that maintenance of
intensive chemotherapy is crucial for increasing overall survival.
Thus, we have
studied in a clinically relevant canine model whether genetic chemoprotection
mediated by methylguanine methyltransferase (MGMT) could circumvent this
limitation.
Methods. CD34-enriched donor marrow cells were transduced with a retroviral
vector encoding the P140K mutant of the DNA-repair enzyme MGMT and enhanced
green fluorescent protein (EGFP).
Transduced cells were infused into recipients
after myeloablative irradiation.
Gene marking in hematopoietic repopulating
cells was assessed by flow cytometry and real-time PCR.
Results. In the first dog, 5 mg/kg O6BG and 0.4 mg/kg BCNU were adminstered at
16 weeks after transplantation.
The proportion of gene-modified cells rose in
all lineages (granuloctes from 15% to about 60% and platelets from 9% to 40%).
After 12 months, we retreated the dog with an identical dose of O6BG and BCNU.
In contrast to the first drug cycle, which was associated with prolonged
thrombocytopenia, there was no myelosuppression associated with the second cycle
of chemotherapy, indicating whetsuccessful marrow protection.
These results were
confirmed in a second dog.
In 2 additional dogs we studied whether
MGMT-transduced stem cells would also mediate chemoprotection with O6BG and
temozolomide.
After several cycles with slowly escalating drug doses, more than
80% of granulocytes and platelets expressed MGMT.
When these animals received 5
mg/kg O6BG and 500 mg/m2 of temozolomide, a dose that causes substantial
thrombocytopenia in control dogs (platelets < 15,000 / ul), no significant
myelsuppression was observed.
Extrahematopoietic toxicity of these treatments
was minimal, and all dogs are alive and well.
Conclusions. These data from a clinically relevant canine model demonstrate that
MGMT(P140K)-transduced stem cells can provide effective marrow protection from
intensive chemotherapy.
These findings should have important implications for
the use of dose-dense or dose-intensive chemotherapy in patients with malignant
diseases.
Copyright © 2004 American Association for Cancer Research.
All rights reserved.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=200284
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