Adenoviral Transduction of Human Acid Sphingomyelinase into Neo-angiogenic Endothelium Radiosensitizes Tumor Cure

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Aug 13

PMID 23936314

Citations 17

Authors

Branka Stancevic

Nira Varda-Bloom

Jin Cheng

John D Fuller

Jimmy A Rotolo

Monica Garcia-Barros

Regina Feldman

Shyam Rao

Ralph R Weichselbaum

Dror Harats

Adriana Haimovitz-Friedman

Zvi Fuks

Michel Sadelain

Richard Kolesnick

Affiliations

Soon will be listed here.

Abstract

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.

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