Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.
These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x), and a hypoxia-inducible dual-binding HIF-2α-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x)-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x)-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x)-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Branka
B
Stancevic
Nira
N
Varda-Bloom
Jin
J
Cheng
John D
JD
Fuller
Jimmy A
JA
Rotolo
Mónica
M
García-Barros
Regina
R
Feldman
Shyam
S
Rao
Ralph R
RR
Weichselbaum
Dror
D
Harats
Adriana
A
Haimovitz-Friedman
Zvi
Z
Fuks
Michel
M
Sadelain
Richard
R
Kolesnick
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D005354:Fibrosarcoma / Q000201:enzymology / Q000517:prevention & control* / Q000532:radiotherapy; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008546:Melanoma, Experimental / Q000201:enzymology / Q000517:prevention & control* / Q000532:radiotherapy; D051379:Mice; D009389:Neovascularization, Pathologic; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
D011838:Radiation-Sensitizing Agents; D013108:Sphingomyelin Phosphodiesterase