A Model for NAD(P)H:Quinoneoxidoreductase 1 (NQO1) Targeted Individualized Cancer Chemotherapy

• Published in: Drug target insights Vol. 2009; no. 4; pp. DTI.S1146 - 8
• Main Authors: Begleiter, Asher, El-Gabalawy, Nadia, Lange, Laurie, Leith, Marsha K., Guziec, Lynn J., Guziec, Frank S.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publishing 2009; SAGE Publications; AboutScience Srl
• Subjects: benzoquinone mustard; NQO1; tumor targeting; individualized cancer chemotherapy; bioreductive agents
• ISSN: 1177-3928; 1177-3928
• DOI: 10.4137/DTI.S1146

Asher Begleiter1, Nadia El-Gabalawy2, Laurie Lange2, Marsha K. Leith2, Lynn J. Guziec3 and Frank S. Guziec Jr31Manitoba Institute of Cell Biology, CancerCare Manitoba, Departments of Internal Medicine and Pharmacology and Therapeutics, University of Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9 Canada. 2Manitoba Institute of Cell Biology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9 Canada. 3Department of Chemistry and Biochemistry, Southwestern University, Georgetown, Texas 78628 U.S.A.AbstractNQO1 (NAD(P)H:quinoneoxidoreductase 1) is a reductive enzyme that is an important activator of bioreductive antitumor agents. NQO1 activity varies in individual tumors but is generally higher in tumor cells than in normal cells. NQO1 has been used as a target for tumor specific drug development. We investigated a series of bioreductive benzoquinone mustard analogs as a model for NQO1 targeted individualized cancer chemotherapy. We compared the tumor cell growth inhibitory activity of benzoquinone mustard analogs with sterically bulky groups of different size and placed at different positions on the benzoquinone ring, using tumor cell lines with different levels of NQO1. We demonstrated that functional groups of different steric size could be used to produce a series of bioreductive antitumor agents that were activated by different levels of NQO1 in tumor cells. This series of drugs could then be used to target cells with specific levels of NQO1 for growth inhibition and to avoid damage to normal cells, like bone marrow cells, that have low levels of NQO1. This approach could be used to develop new bioreductive antitumor agents for NQO1 targeted individualized cancer chemotherapy.