title: Optical imaging of treatment-related tumor cell death using a heat shock protein-90 alkylator.
abstract: The ability to assess in near-real time the tumor cell killing efficacy of chemotherapy regimens would improve patient treatment and survival. An ineffective regimen could be abandoned early in favor of a more effective treatment. We sought to noninvasively image treatment-related tumor cell death in mice using an optically labeled synthetic heat shock protein-90 (Hsp90) alkylator, 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO). The Hsp90 chaperone is an important element in oncogene addiction and tumor cell survival, and its expression is enhanced by chemotherapy. These factors were predicted to favor the detection of tumor cell death using GSAO. GSAO specifically labeled apoptotic and necrotic tumor cells in culture and cells of comparable morphology in subcutaneous human pancreatic carcinoma tumors in mice. A near-infrared fluorescent conjugate of GSAO was used to noninvasively image cyclophosphamide-induced tumor cell death in murine orthotopic human mammary tumors. The GSAO conjugate did not accumulate in healthy organs or tissues in the mouse, and unbound compound was excreted rapidly via the kidneys. There was a significant increase in the GSAO fluorescence signal in the treated tumors measured either in vivo or ex vivo, and the fluorescence signal colocalized with apoptotic cells in sectioned tumors. The favorable biodistribution of optically labeled GSAO, the nature of its tumor cell target, and its capacity to noninvasively detect tumor cell death should facilitate the application of this compound in studies of the efficacy of existing and new chemotherapeutics.
authors: Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales , Sydney, New South Wales 2052, Australia.
authors: Danielle
authors: D
authors: Park
authors: Bang-Wen
authors: BW
authors: Xie
authors: Ermond R
authors: ER
authors: Van Beek
authors: Vicky
authors: V
authors: Blankevoort
authors: Ivo
authors: I
authors: Que
authors: Clemens W G M
authors: CW
authors: Löwik
authors: Philip J
authors: PJ
authors: Hogg
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018841:HSP90 Heat-Shock Proteins; D003520:Cyclophosphamide