Charles B. Grissom

Professor of Chemistry

Chuck Grissom

B.A. University of California, Riverside

Ph.D. University of Wisconsin, Madison

Research

References

grissomc@chemistry.utah.edu

Chuck Grissom's Lab Page

Charles Grissom's PubMed Literature Search

Biological Chemistry Program

Cancer Drug Delivery and Enzyme Mechanisms

Research

Targeted Delivery of Cancer Drugs
Our laboratory has developed a new method to target the delivery of cytotoxic anticancer drugs and fluorescent tumor imaging agents to tumor cells by using vitamin B12 as a "Trojan Horse" delivery vehicle.   Drug-B12 bioconjugates are synthesized by attaching various cytotoxic warheads to cobalamin.   The pro-drug is nontoxic until it is internalized by the cancer cell and activated by an intracellular enzyme.   Results in vitro and in vivo show this "Trojan Horse" strategy for targeted drug delivery to be a very effective method to increase the therapeutic index of anticancer drugs.   Rapidly dividing cells require coenzyme B12 for thymidine synthesis prior to DNA replication.   Elevated levels of cobalamin and cobalamin transport proteins are observed in many patients with leukemia and various solid tumors.

Cancer Diagnostics and Fluorescent Tumor Imaging Agents
A fluorescent conjugates of cobalamin (CobalaFluor) show promise as imaging agents for breast cancer surgery and other diagnostic procedures where it is desirable to visualize tumors and metastatic cancer cells.   Accompanying instrumentation has been developed that may allow axillary lymph node dissection in breast cancer surgery to be carried out with minimally-invasive endoscopic techniques.   These applications are being evaluated in collaboration with surgeons and pathologists at the University of Utah.

Visualization of Intracellular Cobalamin Trafficking
Fluorescent cobalamin analogs can also be used to explore the intracellular trafficking of cobalamin as it enters the cell through receptor-mediated endocytosis and is transported through the lysosome to the cytosol.  Single molecules of fluorescent cobalamin can be imaged and followed through cellular processes.

Projects for Graduate Students
Graduate students have the ability to define their own project within the spectrum of cobalamin-targeted imaging agents and drug delivery.   Students can design, synthesize, and test new bioconjugates of cancer drugs.   Since this project is a collaboration with research groups in the Chemistry, Pharmacology, Pathology, and Surgery Departments of the University of Utah Medical School, students can participate in every aspect of therapeutic drug development and biological evaluation.   This unusual opportunity in an academic setting provides a broad graduate education, with solid training in biological chemistry.

Vitamin B12 Dependent Enzymes and Magnetic Field Effects on Electron Transfer
Our laboratory is also studying the mechanism of enzymes with radical pair intermediates, especially B12 -dependent enzymes.   We have developed new methods for probing the mechanism of biological and chemical reactions using magnetic fields and heavy atoms.   Only reactions that produce a radical pair intermediate are influenced by an external magnetic field or a heavy atom (such as xenon).   We reported the first magnetic field effect on an enzymatic reaction (B12 dependent ethanolamine ammonia lyase). This finding is significant because it confirms the existence of a kinetically-significant radical pair intermediate in enzymatic catalysis and it provides a mechanism by which magnetic fields can interact with specialized biological systems. We have extended our studies to horseradish peroxidase, a heme-containing enzyme that is also magnetic field dependent.

Grissom Figure Two

References

  1. Lee M, Grissom CB (2009) Design, synthesis, and characterization of fluorescent cobalamin analogues with high quantum efficiencies. Org Lett 11(12):2499-502
  2. Bagnator JD, Eilers AL, Horton RA, Grissom CB (2009) Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin. J Org Chem 69(26):8987-96
  3. Horton RA, Bagnato JD, Grissom CB (2004) Synthesis and Characterization of a Cobalamin-Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin.   J. Org. Chem. 69:8987-8996
  4. Horton RA, Bagnato JD, Grissom CB (2003) Structural Determination of 5'-OH a-Ribofuranoside Modified Cobalamins via 13C and DEPT NMR.   J. Org. Chem. 68:7108-7111
  5. McGreevy JM, Cannon M, Grissom CB (2003) Minimally-Invasive Nodal Dissection in Pigs using Fluorescently-Labelled Cobalamin.   J. Surg. Res. 111:38-44
  6. Cannon MJ, Myszka DG, Bagnato JD, Alpers DH, West FG, Grissom CB (2002) Affinity and Kinetic Analysis of the Interactions between Vitamin B12 Binding Proteins and Cobalamins by Surface Plasmon Resonance.   Analytical Biochemistry 305:1-9
  7. Anderson MA, Xu Y, Grissom CB (2001) Electron Spin Catalysis by Xenon in an Enzymatic Reaction.   J. Am. Chem. Soc. 123:6720-6721
  8. Smeltzer C, Cannon MJ, Pinson P, Munger JS, West FG, Grissom CB (2001) Synthesis and Characterization of Fluorescent Cobalamin (CobalaFluor) Derivatives for Imaging.   Org. Lett. 3:799-801

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Last Updated: 11/7/16