Dr. Kohn received an M. D. degree from Columbia College of Physicians and Surgeons in 1956 and a Ph. D. in Biochemistry and Molecular Biology from Harvard in 1965. He came to the National Cancer Institute as a Clinical Associate in 1957 and has served as Chief of the Laboratory of Molecular Pharmacology since 1968. His major area of investigation has been the mechanisms of action of DNA-targeted anticancer drugs. He developed the DNA filter elution methodology to measure DNA damage in mammalian cells, and showed that DNA topoisomerases are targets of action of clinical anticancer drugs. His recent research interest is to apply the emerging knowledge of cell cycle control networks to possible new modes of therapy.
Determinants of Cancer Cell Chemosensitivity
Much of this work is collaborative with the groups led by Drs. Yves Pommier, Patrick O'Connor, and John Weinstein in this Laboratory. A premise of these investigations is that the molecular regulatory defects that make cancer cells malignant also are likely to make them susceptible to specific kinds of metabolic stress. We are therefore working to understand the bases and consequences of the regulatory abnormalities, and to search for new compounds or therapeutic strategies that could take advantage of those abnormalities.
Cell cycle regulation
After many years of studying the production and repair of DNA damage consequent upon treatment of cells with cancer chemotherapeutic drugs, recent progress led us to the conviction that the occasional effectiveness of these types of therapies is due to regulatory defects in cancer cells, especially in regard to cell cycle checkpoints. We are therefore now investigating the checkpoint response mechanisms in cells that have specific molecular abnormalities. We are studying the molecular and biological events that follow treatment with drugs having known mechanisms of action, as described herein by Dr. O'Connor. As an aid to the design of functional experiments based on current knowledge of cell cycle control with its complex molecular regulatory networks, we have recently devised a self-consistent grammar of interaction diagrams that could facilitate computer simulations.
The concept of DNA topoisomerases as targets of anticancer drugs originated in this Laboratory in the course of systematic investigations of DNA lesions produced by many different agents and studied by means of our DNA filter elution techniques. We are investigating several aspects of the mechanism of lesion formation due to drugs that block topoisomerases on DNA, as well as the consequences of such blockages to the cell, as described herein by Dr. Pommier. We found that the sites of lesion formation on the DNA have base sequence preferences that are characteristic for each structural class of topoisomerase-targeted drug. This led us to a structural hypothesis of the drug-DNA-topoisomerase complexes, which in turn led recently to the synthesis of a new camptothecin derivative that, in addition to complexing with topoisomerase I, alkylates the DNA at the site of the complex. Studies of cell death caused by topoisomerase-targeted drugs recently led us to devise a sub-cellular system for the study of apoptosis.
We have been investigating potential inhibitors of HIV integrase, an enzyme that is essential in the life cycle of the virus. We initiated this investigation because of a general analogy of mechanism between this enzyme and topoisomerases. Using an assay system devised by Dr. Robert Cragie and his coworkers, we were first to publish findings on inhibitors of retroviral integrase. Some highlights of this work are described herein by Dr. Pommier. Based on extensive structure-activity studies, we have deduced a pharmacophore basis of the inhibition that holds for several chemical classes of inhibitors.
Clues from cytotoxicity data on characterized human cancer cell lines
With Dr. Weinstein's group, we are searching for correlates between cytotoxicity and molecular abnormalities existing in various human cancer cell lines. Confirmed cytotoxicity data has accumulated on several thousand compounds tested against a panel of 60 human tumor cell lines in the NCI cancer screen. The cell lines are being characterized with respect to abnormalities in protooncogenes, tumor suppressor genes, and cell cycle checkpoint responses. We have developed computer programs to search for possible relationships between molecular abnormalities and sensitivity to tested compounds. Drug candidates derived in this way would be predicted to act selectively against tumors that possess the specific molecular abnormalities. Internally consistent correlations have been demonstrated for compounds of related chemical structure or similar action mechanism, thus indicating that the data base is rich in information.
Keywords: cancer cell growth regulation, cell cycle, chemotherapy, theoretical biology
Selected recent publications: