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

Asher Begleiter; Nadia El-Gabalawy; Laurie Lange; Marsha K. Leith; Lynn J. Guziec; Frank S. Guziec Jr

doi:10.33393/dti.2009.1337

Authors

Asher Begleiter Manitoba 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.
Nadia El-Gabalawy Manitoba Institute of Cell Biology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9 Canada.
Laurie Lange Manitoba Institute of Cell Biology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9 Canada.
Marsha K. Leith Manitoba Institute of Cell Biology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9 Canada.
Lynn J. Guziec Department of Chemistry and Biochemistry, Southwestern University, Georgetown, Texas 78628 U.S.A.
Frank S. Guziec Jr Department of Chemistry and Biochemistry, Southwestern University, Georgetown, Texas 78628 U.S.A.

DOI:

https://doi.org/10.33393/dti.2009.1337

Keywords:

individualized cancer chemotherapy, tumor targeting, bioreductive agents, NQO1, benzoquinone mustard

Abstract

NQO1 (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.