Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies

Andrew M. Evens*, Lakshmi Balasubramanian, Leo I. Gordon

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

16 Scopus citations

Abstract

Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies. Motexafin gadotinium (MGd) is a synthetic expanded porphyrin that selectively accumulates in tumor cells and oxidizes various intracellular metabolites, including ascorbate, nicotinamide adenine dinucleotide phosphate, glutathione, and protein thiols, to generate reactive oxygen species in a process known as futile redox cycling. The rationale for its use in hematologic malignancies is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells, and it has a novel mechanism of action of inducing redox stress and triggering apoptosis in a broad range of malignancies. MGd induces apoptosis in B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and highly resistant myeloma cell lines. Furthermore, MGd is additive or synergistic with ionizing radiation, several chemotherapy agents, and rituximab in vitro and in vivo tumor models. Through gene expression profiling, various stress-related genes are upregulated in response to MGd, including genes encoding metallothioneins, heat shock proteins, and heme oxygenase. Preliminary results from clinical trials with MGd in hematopoietic malignancies have shown that it is well tolerated, with minimal hematologic side effects in both; it has single agent activity in very heavily pretreated chronic lymphocytic leukemia /small lymphocytic lymphoma patients, and it has induced prompt complete remissions in combination with 90Yttrium-ibritumomab (Y-90 Zevalin; Biogen Idec Inc., Cambridge, MA) for relapsed non-Hodgkin's lymphoma in the first two cohorts of patients enrolled. Various clinical trials studying MGd as a single agent and in combination with radiation and/or chemotherapy for the treatment of hematologic malignancies are ongoing.

Original languageEnglish (US)
Pages (from-to)289-296
Number of pages8
JournalCurrent treatment options in oncology
Volume6
Issue number4
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies'. Together they form a unique fingerprint.

Cite this