title: Monitoring of tumor response to chemotherapy in vivo by a novel small-molecule detector of apoptosis.
abstract: Utilization of molecular imaging of apoptosis for clinical monitoring of tumor response to anti-cancer treatments in vivo is highly desirable. To address this need, we now present ML-9 (butyl-2-methyl-malonic acid; MW = 173), a rationally designed small-molecule detector of apoptosis, based on a novel alkyl-malonate motif. In proof-of-concept studies, induction of apoptosis in tumor cells by various triggers both in vitro and in vivo was associated with marked uptake of (3)H-ML-9 administered in vivo, in correlation with the apoptotic hallmarks of DNA fragmentation, caspase-3 activation and membrane phospholipid scrambling, and with correlative tumor regression. ML-9 uptake following chemotherapy was tumor-specific, with rapid clearance of the tracer from the blood and other non-target organs. Excess of non-labeled "cold" compound competitively blocked ML-9 tumor uptake, thus demonstrating the specificity of ML-9 binding. ML-9 may therefore serve as a platform for a novel class of small-molecule imaging agents for apoptosis, useful for assessment of tumor responsiveness to treatment.
authors.affiliation: Aposense Ltd., 5 Ha'Odem Street, Petach-Tiqva, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Grimberg
authors.forename: Galit
authors.initials: G
authors.lastname: Levin
authors.forename: Anat
authors.initials: A
authors.lastname: Shirvan
authors.forename: Avi
authors.initials: A
authors.lastname: Cohen
authors.forename: Merav
authors.initials: M
authors.lastname: Yogev-Falach
authors.forename: Ayelet
authors.initials: A
authors.lastname: Reshef
authors.forename: Ilan
authors.initials: I
authors.lastname: Ziv
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002330:Carmustine / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use; D016903:Drug Monitoring; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D008314:Malonates / Q000737:chemistry; D008764:Methylmalonic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D008314:Malonates; C539744:butyl-2-methyl-malonic acid; D004317:Doxorubicin; D008764:Methylmalonic Acid; C030290:malonic acid; D005472:Fluorouracil; D002330:Carmustine