Monitoring of tumor response to chemotherapy in vivo by a novel small-molecule detector of apoptosis

Apoptosis. 2009 Mar;14(3):257-67. doi: 10.1007/s10495-008-0293-7.


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.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / therapeutic use
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Apoptosis*
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Carmustine / therapeutic use
  • Cell Line, Tumor
  • Doxorubicin / therapeutic use
  • Drug Monitoring*
  • Fluorouracil / therapeutic use
  • Humans
  • Jurkat Cells
  • Malonates / chemistry
  • Methylmalonic Acid / analogs & derivatives*
  • Methylmalonic Acid / analysis
  • Methylmalonic Acid / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / chemistry
  • Neoplasms / drug therapy*
  • Neoplasms / pathology


  • Antibiotics, Antineoplastic
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents, Alkylating
  • Biomarkers
  • Malonates
  • butyl-2-methyl-malonic acid
  • Doxorubicin
  • Methylmalonic Acid
  • malonic acid
  • Fluorouracil
  • Carmustine